Processes for the preparation of substituted propenone derivatives

ABSTRACT

Industrial and commercial processes for the preparation of 2-acyl-5-benzylfuran derivatives, 1,2,4-triazole-3-carboxylic acid ester derivatives or propenone derivatives having an anti-HIV activity; and useful crystals of the derivatives. A deblocking: (III-2), (IV-10), (VI-1), wherein R 1 , R 2  and R 4  are each independently hydrogen or the like; A is CR 6  or N; R 6  is hydrogen or the like; Q is a protecting group; and L is a leaving group.

This application is a 371 of PCT/JP00/03456 filed May 29, 2000.

TECHNICAL FIELD

The present invention relates to processes for the preparation of novelsubstituted propenone derivatives and their crystals, in detailprocesses for the preparation of their intermediates,2-acyl-5-benzylfuran derivatives and 1,2,4-triazole-3-carboxylic acidester derivatives.

BACKGROUND ART

2-Acyl-5-alkylfuran derivatives, which are similar to2-acyl-5-benzylfuran derivatives, can be prepared by introducing an acylgroup to 2-alkyfuran derivatives through Friedel Crafts reaction(Japanese Patent Publication (Kokoku) 1995-78056, Japanese PatentPublication (Kokoku) 1995-78056 and Japanese Patent Publication (Kokai)1986-53275).

2-Alkylfuran derivatives can be prepared by introducing an alkyl groupto furan derivatives through Priedel Crafts reaction (Chem. France.1962, 1166).

However, the preparation of 2-acyl-5-benzylfuran derivatives is notdisclosed in these documents.

On the other hand, it is known that 1,2,4-triazole-3-carboxylic acid canbe prepared by converting an amino group of3-amino-1,2,4-triazole-5-carboxylic acid to a diazo group, isolating thediazonium salt and reducing.

It is known as a reducing method that 1) a diazonium salt is reducedwith sodium hypophosphite (NaH₂PO₂) and concentrated hydrochloric acid(HCl) under 15° C. (Khim. Geterotsikl. Soedin., 1967, 180-183) and 2) adiazonium salt is reduced at 45 to 50° C. in methanol (Khim.Geterotsikl. Soedin., 1965, 624-626).

In is known as a deaminating method of 3-amino-1,2,4-triazole thatdiazonation and reduction are carried out at the same time (J. Am. Chem.Soc. 76, 290, 1954).

As another process, 1,2,4-triazole-3-carboxylic acid ester can beprepared by heating acylamidrazone over its melting point (150 to 200°C.) to cyclize (Collect. Czech. Chem. Commun., 49, 1984, 2492-2495, J.Heterocyclic Chem., 25, 651-654, 1998). The document describes that alarge scale of cyclization must be preformed under reduced pressure withheating over its melting point for removing the generated water.

DISCLOSURE OF INVENTION

A compound of the formula (VI-1):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; A is CR⁶ orN; and R⁶ is hydrogen, optionally substituted alkyl or optionallysubstituted aryl, has an anti-HIV activity by inhibiting HIV integrase.

A compound of the formula (VI-1) can be prepared in the followingmethod.

wherein R¹, R², R⁴ and A are as defined above; Q is a protecting group;and L is a leaving group.

Industrial and commercial preparations of 2acyl-5-benzylfuranderivatives and 1,2,4-triazole-3-carboxylic acid ester derivatives,which are useful intermediates of the compound (VI-1), are desired.

First, the preparation of 2-acyl-5-benzylfuran derivatives is describedbelow.

As a conventional route, for example, the following methods can bethought.

wherein any ring may be substituted with optionally substituted alkyl,optionally substituted alkoxy and/or halogen.

In method X, 2-furoic acid, a starting material is reacted withbenzaldehyde. After removing the hydroxy group from the obtainedcompound, the carboxy group is esterified to give 2-pyridine thioester,which is reacted with methyl magnesium bromide to give2-acetyl-5-benzylfuran. This method requires 2-pyridine thioester whichis removed at the following step for converting the carboxy group toacetyl.

In method Y, furfural, a starting material, is reacted with phenylmagnesium bromide. After removing the hydroxy group of the obtainedcompound, 2-acetyl-5-benzylfuran is prepared through Friedel Craftsreaction. The final step of this method requires Friedel Crafts reactionwhich must be carried out under acidic condition. However, 2-benzylfuranis unstable under acidic condition, so 2-acyl-5-benzylfuran can not beprepared in high yield.

Since both of methods X and Y require many steps and many reagents,2-acetyl-5-benzylfuran derivatives can not be industrially andcommercially prepared.

The present inventors have solved the above problems on methods X and Y,and found out industrial and commercial processes for the preparation of2-acyl-5-benzylfuran derivatives can be achieved through Friedel Craftsreaction of 2-acylfuran derivatives.

The present inventions of 2-acsyfuran derivatives include;

A-1) a process for the preparation of a compound of the formula (III-1):

wherein R¹ and R² each is independently hydrogen, optionally substitutedalkyl, optionally substituted alkoxy or halogen; R³ is optionallysubstituted alkyl or optionally substituted alkoxy; and R⁴ is hydrogen,optionally substituted alkyl, optionally substituted alkoxy or halogen,which comprises reacting a compound of the formula (I-1):

wherein R¹, R² and R³ each is as defined above,

with a compound of the formula (II-1):

wherein R⁴ is as defined above; and X is halogen,

in the presence of a Lewis acid,

A-2) the process according to the above A-1) wherein a reaction solventis methylene chloride,

A-3) the process according to the above A-1) wherein a reaction solventis water,

A-4) the process according to any one of the above A-1) to A-3) whereinR³ is methyl,

A-5) the process according to any one of the above A-1) to A-4) whereinR¹ and R² each is hydrogen, and

A-6) the process according to any one of the above A-1) to A-5) whereinR⁴ is 4-fluoro.

Second, the preparation of 1,2,4-triazole-3-carboxylic acid esterderivatives is described below.

A conventional process for the preparation of 1,2,4-triazole-3-carboxlicacid comprising a reduction of an isolated diazonium salt is accompaniedwith danger of explosion when a large amount of a diazonium salt istreated, so this process is not suitable to industrial production.

A process for the preparation of 1,2,4-triazole-3-carboxilic acid estercomprising a cyclization of acylamidrazone requires heating over amelting point, so this process is not suitable in an industrial scale,too.

Then, the present inventors have solved the above problems and found outprocesses for the preparation of 1,2,4-triazole-3-carboxilic acid esterderivatives as shown below, which are suitable in an industrial scale.

The present inventions of 1,2,4-triazole-3-carboxilic acid esterderivatives include;

B-1) a process for the preparation of a compound of the formula (IV-2):

wherein R⁵ is hydrogen or optionally substituted alkyl,

which comprises reacting a compound of the formula (IV-1):

wherein R⁵ is as defined above,

with an alkaline metal nitrite or an alkaline-earth metal nitrite in thepresence of a reducing agent,

B-2) the process according to the above B-1) which comprises reacting acompound of the formula (IV-1) with an alkaline metal nitrite in thepresence of hypophosphorous acid as the reducing agent,

B-3) the process according to the above B-1) or B-2) which is carriedout under the addition of a small amount of alchol,

B-4) the process according to any one of the above B-1) to B-3) whereinR⁵ is hydrogen,

B-5) a process for the preparation of a compound of the formula (IV-3):

wherein R⁵ is optionally substituted alkyl,

which comprises preparing 1,2,4-triazole-3-carboxilic acid through theprocess according to the above B-4) and esterifing the obtainedcompound,

B-6) a process for a compound of the formula (IV-43):

wherein R⁵ is hydrogen or optionally substituted alkyl; and R⁶ ishydrogen,

optionally substituted alkyl or optionally substituted aryl,

which comprises cyclizing a compound of the formula (V):

wherein R⁵ and R⁶ are as defined above,

in the presence of trialkylorthoester or a catalytic amount of an acid,

B-7) the process according to the above B-6) wherein R⁵ is optionallysubstituted alkyl,

B-8) the process according to the above B-6) wherein R⁵ is optionallysubstituted alkyl; and R⁶ is hydrogen,

B-9) a process for the preparation of a compound of the formula (IV-6):

wherein R⁵ is optionally substituted alkyl; R⁶ is hydrogen, optionallysubstituted alkyl or optionally substituted aryl; and R¹² is a group ofthe formula: —R⁷ wherein R⁷ is trityl, optionally substituted sulfamoylor optionally substituted alkoxymethyl, a group of the formula:—C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is optionally substituted alkyl; R⁹, R¹⁰and R¹¹ each is independently hydrogen or optionally substituted alkyl;or R⁵ and R¹⁰ may be taken together to form optionally substitutedalkylene, or hydroxymethyl, which comprises preparing a compound of theformula (IV-5):

wherein R⁵ and R⁶ are as defined above, through the process according toany one of the above B-1) to B-3) and B-5) to B-8), and reacting theobtained compound with a compound of the formula: R⁷X wherein R⁷ is asdefined above; and X is halogen, a compound of the formula:(R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ are as defined above, orformaldehyde,

B-10) a process of the preparation of a compound of the formula (IV-8):

wherein R⁶ is hydrogen, optionally substituted alkyl or optionallysubstituted aryl; and R¹² is a group of the formula: —R⁷ wherein R⁷ istrityl, optionally substituted sulfamoyl or optionally substitutedalkoxymethyl, a group of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ isoptionally substituted alkyl; R⁹, R¹⁰ and R¹¹ each is independentlyhydrogen or optionally substituted alkyl, or R⁸ and R¹⁰ may be takentogether to form optionally substituted alkylene, or hydroxymethyl,which comprises preparing a compound of the formula:(IV-7):

wherein R⁶ is as defined above, through the process according to theabove B-4) or B-6), and reacting the obtained compound with a compoundof the formula: R⁷X wherein R⁷ is as defined above; and X is halogen, acompound of the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹are as defined above, or formaldehyde,

B-11) the process according to the above B-9) or B-10) which comprisesreacting a compound of the formula (IV-7) with a compound of theformula: R⁷X wherein R⁷ is trityl,

B-12) the process according to the above B-9) or B-10) which comprisesreacting a compound of the formula (IV-7) with a compound of theformula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁵ and R¹⁰ are taken together to formtrimethylene; and R⁹ and R¹¹ a hihydrogen,

B-13) the process according to the above B-9) or B-10) which comprisesreacting a compound of the formula (IV-7) with a compound of theformula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸ and R⁹ each is methyl; and R¹⁰ andR¹¹ each is hydrogen,

B-14) a compound of the formula (IV-9):

wherein R⁶ is hydrogen or alkyl; R¹³ is alkyl, a group of the formula:—R⁷ wherein R⁷ is trityl, optionally substituted sulfamoyl oralkoxymethyl, a group of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ isalkyl; R⁹, R¹⁰ and R¹¹ each is independently hydrogen or alkyl; or R⁸and R¹⁰ may be taken together to form alkylene, or hydroxymethyl; andR¹⁴ is a group of the formula: —R⁷ wherein R⁷ is as defined above, agroup of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ aredefined above, or hydroxymethyl, provided that a compound wherein R⁶ ishydrogen; R¹³ is methyl; and R¹⁴ is trityl, a compound wherein R⁶ ishydrogen; R¹³ is methyl; and R¹⁴ is tetrahydropyran-2-yl, and a compoundwherein R⁶ is hydrogen; R¹³ is ethyl; and R¹⁴ is trityl are excluded,

B-15) the compound according to the above B-14) wherein R⁶ is hydrogen;

R¹³ is methyl or ethyl; and R¹⁴ is tetrahydropyran-2-yl, hydroxymethyl,methoxymethyl, ethoxymethyl, N,N-dimethylsulfamoyl,(1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl, (1ethoxy-1-methyl)ethyl,(1-n-propoxy)ethyl, (1-n-butoxy)ethyl or (1-isobutoxy)ethyl.

The present inventions for the preparation of substituted propenonederivatives accompanied by the above A) and/or B) include;

C-1) a process for the preparation of a compound of the formula (VI-1):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; A is CR⁶ orNA; and R⁶ is hydrogen, optionally substituted alkyl or optionallysubstituted aryl, which comprises preparing a compound of the formula(III-2):

wherein R¹, R² and R⁴ are as defined above, through the processaccording to the above A-4), reacting the compound of the formula(III-2) with a compound of the formula (IV-10):

wherein A is as defined above, Q is a protecting group; and L is aleaving group, in the presence of a base, and deprotecting Q,

C-2) the process according to the above C-1) wherein R¹ and R² each ishydrogen; and R⁴ is halogen,

C-3) the process according to the above C-1) or C-2) wherein R⁴ is4-fluoro,

C-4) the process according to any one of the above C-1) to C-3) whereinA is CH,

C-5) a process for the preparation of a compound of the formula (IV-2):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted, alkyl, optionally substituted alkoxy or halogen; and R⁶ ishydrogen, optionally substituted alkyl or optionally substituted aryl,which comprises preparing a compound of the formula (IV-11):

wherein R⁶ is as defined above, R¹³ is optionally substituted alkyl, agroup of the formula: —R⁷ wherein R⁷ is trityl, optionally substitutedsulfamoyl or, optionally substituted alkoxymethyl, a group of theformula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is alkyl; R⁹, R¹⁰ and R¹¹ each isindependently hydrogen or optionally substituted alkyl; or R⁸ and R¹⁰may be taken together to form alkylene, or hydroxymethyl; and R¹⁴ is agroup of the formula: —R⁷ wherein R⁷ is as defined above, a group of theformula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ are definedabove, or hydroxymethyl, through the process according to the above B-9)or B-10), reacting the obtained compound with a compound of the formula(III-2):

wherein R¹, R² and R⁴ are as defined above, and deprotecting R¹⁴,

C-6) the process according to the above C-5) which comprises preparingthe compound of the formula (III-2):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen through theprocess according to the above A-4),

C-7) the process according to the above C-5) or C-6) wherein R¹, R² andR⁶ each is hydrogen; and R⁴ is halogen,

C-8) a compound of the formula (VI-7):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; R⁶ ishydrogen, optionally, substituted alkyl or optionally substituted aryl;and R¹⁴ is a group of the formula: —R⁷ wherein R⁷ is trityl, optionallysubstituted sulfamoyl or optionally substituted alkoxymethyl, a group ofthe formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is alkyl; R⁹, R¹⁰ and R¹¹each is independently hydrogen or optionally substituted alkyl; or R⁸and R¹⁰ may be taken together to form alkylene, or hydroxymethyl, and

C-9) the compound according to the above C-8) wherein R⁴ is 4-fluoro;R¹, R² and R⁶ each is hydrogen; and R¹⁴ is trityl, tetrahydropyran-2-yl,hydroxymethyl, methoxymethyl, ethoxymethyl, N,N-dimethylsulfamoyl,(1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl, (1-ethoxy-1-methyl)ethyl,(1-n-propoxy)ethyl, (1-n-butoxy)ethyl or (1-isobutoxy)ethyl.

The present inventions for a crystal of the above novel substitutedpropenone derivative include;

D-1) a crystal of an isomer having a chemical structure of the formula(VI-1):

wherein A is CR⁶ or N; R⁶ is hydrogen, optionally substituted alkyl oroptionally substituted aryl; and R¹, R² and R⁴ each is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkoxy orhalogen, D-2) the crystal according to the above D-1) wherein R¹ and R²each is hydrogen; R⁴ is p-fluoro; and A is CH,

D-3) the crystal according to the above D-2) of which crystal parametersby single crystal X-ray diffraction are unit cell constants a=32.432(2)Å, b=10.886(2) Å, c=7.960(2) Å, α=90.00°, β=90.00°, γ=90.00°, V=2810(1)Å³, Z=8; a space group Pbca; and density of 1.481 g/cm³,

D-4) the crystal according to the above D-2) of which diffraction angles(2θ) of main peaks by powder X-ray diffraction are 20.380, 21.280,21.340, 23.140, 23.360, 23.540, 25.860, 27.460, 27.500, 28.100, 28.180,29.400 and 29.480 (degree),

D-5) a crystal of an isomer having a chemical structure of the formula(VI-4):

wherein A is CR⁶ or N; R⁸ is hydrogen, optionally substituted alkyl oroptionally substituted aryl; and R¹, R² and R⁴ each is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkoxy orhalogen,

D-6) the crystal according to the above D-5) wherein R¹ and R² each ishydrogen; R⁴ is p-fluoro; and A is CH,

D-7) the crystal according to the above D-6) of which crystal parametersby single crystal X-ray diffraction are unit cell constants a=11.9003(7)Å, b=9.7183(5) Å, c=13.2617(8) Å, α=90.00°, β=109.450(4)°, γ=90.00°,V=1446.2(1) Å³ and Z=4; a space group P2₁/n; and density of 1.439 g/cm³,

D-8) the crystal according to the above D-6) of which diffraction angles(2θ) of main peaks by powder X-ray diffraction are 8.760, 19.600,22.080, 23.760, 26.200, 27.580 and 29.080 (degree), and

D-9) a crystal of an isomer of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenoneof which diffraction angles (2θ) of main peaks by powder X-raydiffraction are 10.520, 13.860, 15.680, 18.160, 22.840, 26.180 and28.120 (degree).

Each term to be used in the present specification is explained below.

The term “alkyl” includes C1 to C6 straight or branched alkyl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,n-hexyl, isohexyl or the like. Preferred is methyl or ethyl.

The term “alkylene” includes C2 to C6 straight or branched alkylene, forexample, ethylene, propylene, trimethylene, ethylethylene,tetramethylene or the like. Preferred is trimethylene.

The term “alkoxy” includes C1 to C6 straight or branched alkoxy, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy,tert-pentyloxy, n-hexyloxy, isohexyloxy or the like. Preferred ismethoxy or ethoxy.

The term “alkoxymethyl” includes methyl group substituted with the abovealkyloxy, for example, methoxymethyl, ethoxymethyl, n-propoxymethyl,isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl,tert-butoxymethyl, n-pentyloxymethyl, isopentyloxymethyl,neopentyloxymethyl, tert-pentyloxymetbyl, n-hexyloxymethyl,isohexyloxymethyl or the like. Preferred is methoxy or ethoxymethyl.

The term “aryl” includes C6 to C14 aromatic carbocycle, for example,phenyl, naphthyl, anthryl, phenanthryl or the like. Preferred is phenyl.

The term “halogen” includes fluoro, chloro, bromo or iodo. Preferred inX is chloro or bromo. Preferred in R¹³ is fluoro, especiallypara-substituted fluoro.

The term “trityl” means a group of the formula: —CPh₃ wherein Ph isphenyl.

The term “optionally substituted sulfamoyl” includes unsubstitutedsulfamoyl and sulfamoyl mono- or di-substituted with alkyl, for,example, sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl,N-ethylsulfamoyl, N,N-diethylsulfamoyl or the like.

The substituents of “optionally substituted alkyl”, “optionallysubstituted alkoxymethyl” and “optionally substituted alkylene” includearyl. (e.g., phenyl or the like), cycloalkyl (e.g., cyclopropyl,cyclopentyl, cyclohexyl or the like), cyano, nitro, hydroxy, amino,halogenated alkyl (e.g., trifluoromethyl or the like) or the like.

The substituents of “optionally substituted aryl” include alkyl (e.g,methyl, ethyl or the like), alkenyl (e.g., vinyl, allyl or the like),halogen, hydroxy, alkoxy (e.g., methoxy, ethoxy or the like),halogenated alkyl (e.g., trifluoromethyl or the like), nitro, sulfamoyl,amino, alkyl-substituted amino (e.g., methylamino, dimethylamino or thelike), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl or the like),cyano or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a powder X-ray diffraction chart of a crystal (type I) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 2 shows an infrared absorption spectrum chart of a crystal (type I)of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 3 shows a diffrential scanning calorimetry chart of a crystal (typeI) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 4 shows a powder X-ray diffraction chart of a crystal (type II) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 5 shows an infrared absorption spectrum chart of a crystal (typeII) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 6 shows a diffrential scanning calorimetry chart of a crystal (typeII) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 7 shows a powder X-ray diffraction chart of a crystal (type III) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 8 shows an infrared absorption spectrum chart of a crystal (typeIII) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

FIG. 9 shows a diffrential scanning calorimetry chart of a crystal (typeIII) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventions are explained with the following process A,process B and process C.

First, a process for the preparation of 2-acyl-5-benzylfuran derivativesis explained below.

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; R³ isoptionally substituted alkyl or optionally substituted alkoxy.

This scheme shows a process for the preparation of 2-acyl-5-benzylfuranderivatives (III-1) which comprises reacting 2-acylfuran derivatives(I-1) with benzylhalide derivatives (II-1) in the presence of a Lewisacid through Friedel Crafts reaction.

The compound (I-1) includes 2-acetylfuran, 2-acetyl-3-methylfuran,2-acetyl-4-methylfuran, 2-acetyl-3,4-dimethylfuran,2-acetyl-3-methoxyfuran, 2-acetyl-4-methoxyfuran,2-acetyl-3,4-dimethoxyfuran, 2-acetyl-3-chlorofuran,2-acetyl-4-chlorofuran, 2-acetyl-3,4-dichlorofuran, 2-propionylfuran,3-methyl-2-propionylfuran, 4-methyl-2-propionylfuran,3,4-dimethyl-2-propionylfuran, 3-methoxy-2-propionylfuran,4-methoxy-2-propionylfuran, 3,4-dimethoxy-2-propionylfuran,3-chloro-2-propionylfuran, 4-chloro-2-propionylfuran,3,4-dichloro-2-propionylfuran, methyl 2-furoic acetate, ethyl 2-furoicacetate or the like. Preferred is 2-acetylfuran.

The compound (II-1) includes benzylchloride, benzylbromide,4-methylbenzylchloride, 4-methylbenzylbromide, 4-methoxybenzylchloride,4-methoxybenzylbromide, 4-fluorobenzylchloride, 4-fluorobenzylbromide,4-chlorobenzylchloride, 4-chlorobenzylbromide, 3-methylbenzylchloride,3-methylbenzylbromide, 3-methoxybenzylchloride, 3-methoxybenzylbromide,3-fluorobenzylchloride, 3-fluorobenzylbromide, 3-chlorobenzylchloride,3-chlorobenzylbromide or the like. Preferred is 4-fluorobenzylchlorideor 4-fluorobenzylbromide.

A Lewis acid includes zinc chloride (ZnCl₂), stannic chloride (SnCl₄),ferric chloride (III) (FeCl₃), aluminum chloride (AlCl₃), BF₃/ether orthe like. Preferred is zinc chloride or stannic chloride.

This process can be performed without a reaction solvent. When areaction solvent is used, water, carbon disulfide, methylene chloride,dichloroethane, chloroform or the like can be used. Preferred is wateror methylene chloride.

When methylene chloride is used as a reaction solvent, the producedcompound (III-1) forms a complex with a Lewis acid, a crystal of whichis precipitated in the reaction solvent. The crystal is filtered off,dissolved in water, extracted with an organic solvent to give thecompound (III-1) in high quality.

When water is used as a reaction solvent, the reaction can be performedmildly, which is economically and environmentally preferable.

The reaction temperature is −50 to 150° C., preferably, 0 to 100° C.

The reaction time is 1 to 48 hours, preferably 1 to 24 hours.

2-Acyl-5-benzylfuran derivatives such as a compound (III-1) or (III-2)can be prepared through the following processes such as Process A-2 andA-3 besides the above Process A1.

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen.

The above process includes the following four steps. First, a couplingreaction of a compound (I-2) and (II-2) produces a compound (III-3).Second, a dehydroxy reaction of the compound (III-3) produces a compound(III-4). Third, an introduction of a leaving group to a carboxy group ofthe compound (III-4) produces a compound (III-5). Finally, a reaction ofthe compound (III-5) with methyl magnesium halide (e.g., methylmagnesium bromide) produces a compound (III-2).

The above coupling reaction can be performed in the presence of a base(e.g., LDA) under cooling.

The dehydroxy reaction can be preformed by reduction with trimethylchlorosilane and sodium iodide. This reaction can be performed by ahydrogenation in the presence of palladium carbon after an acetylationwith acetic anhydride in the presence of triethylamine.

The converting of a carboxy group to an acetyl group can be performed bythe following steps. First, a compound (III-4) is reacted withthionylhalide (e.g., thionylchloride) in the presence of a catalyticamount of dimethylformamide or the like. Second, the obtained compoundis reacted with methyl magnesium halide (e.g., methyl magnesiumchloride) in the presence of a catalytic amount of ironic acetylacetonate.

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; and X ishalogen.

The above process for the preparation of a compound (III-2) comprisesreacting a compound (I-3), a starting material, with a compound (II-3),removing a hydroxy group, and Friedel-Crafts reaction.

Second, the process for the preparation of 1,2,4-triazole-3-carboxylicacid ester derivatives is explained below.

wherein R⁵ is hydrogen or optionally substituted alkyl.

This scheme shows a process for the preparation of a compound (IV-2)which includes a deamination of a compound (IV-1), in detail, a directlydeamination without isolating a diazonium salt.

An alkali metal nitrite to-be used includes sodium nitrite, potassiumnitrite, lithium nitrite or the like. Preferred is sodium nitrite.

An alkaline-earth metal nitrite can be used in place of alkali metalnitrite. An alkaline-earth metal nitrite includes calcium nitrite or thelike.

A reducing agent includes hypophosphorous acid (H₃PO₂), phosphorous acid(H₃PO₃), Ca(H₂PO₂)₂, NaBH(OAc)₃, PhSH, H₂CO or the like. Preferred ishypophosphorous acid (H₃PO₂).

To a compound (IV-1) is added an aqueous solution of a reducing agent(e.g., hypophosphorous acid) and warmed at 30 to 60° C. (preferably, 40to 50° C.). To the suspension is added dropwise under stirring at 30 to60° C. (preferably, under 50° C.) for approximately 10 to 60 minutes(preferably approximately 30 minutes) an aqueous solution of an alkalimetal nitrite or an alkaline-earth metal nitrite. After addition, thereaction mixture is stirred at the same temperature for 10 to 60 minutes(preferably 30 minutes), cooled to 0-20° C. (preferably, approximately5° C.) and stirred for 10 to 60 minutes (preferably, approximately 30minutes). The objective, a compound (IV-2) can be prepared by filteringthe obtained suspension.

This process may be performed in the presence of a diluted hydrochloricacid (e.g., 6% hydrochloric acid) or the like.

Preferred in this process is an addition of a small amount (1-10 (v/v)%, preferably, 2-3 (v/v) % to all volume of a solvent to be used, orapproximately 0.2 mole equivalent to a compound (I)) of alcohol. A gasis produced for approximately 10 minutes by adding an aqueous solutionof an alkali metal nitrite. An addition of alcohol suppresses a vigorousproduction of the gas as well as controlling the adding rate of anaqueous solution of an alkali metal nitrite.

An alcohol includes an alkyl alcohol, for example, isopropylalcohol,isobutanol, methanol, ethanol, n-propylalcohol, n-butanol or the like.Preferred is isopropylalcohol or isobutanol.

A compound (IV-1) includes 3-amino-1,2,4-triazole-5-carboxylic acid andits alkyl ester derivatives (e.g., 3-amino-1,2,4-triazole-5-carboxylicacid methyl ester, 3-amino-1,2,4-triazole-5-carboxylic acid ethylester). Preferred is a compound wherein R⁵ is hydrogen,3-amino-1,2,4-triazole-5-carboxylic acid.

When a compound (IV-1) is an alkyl ester derivative of3-amino-1,2,4-triazole-5-carboxylic acid, the reaction temperatureshould be controlled for preventing its ester part from converting tocarboxylic acid.

wherein R⁵ is optionally substituted alkyl.

This scheme shows a process for the preparation of a compound (IV-3)which comprises esterifing 1,2,4-triazole-3-carboxylic acid preparedthrough the process B1 wherein R¹ is hydrogen.

A carboxylic acid can be esterified in accordance with the usual mannerof reacting it with alcohol in the presence of an acid catalyst.

To a solution of 1,2,4-triazole-3-carboxylic acid in alcohol (e.g.,methanol, ethanol, n-propanol, n-butanol, benzylalcohol) is addeddropwise under cooling with stirring, thionylhalide (e.g.,thionylchloride, thionylbromide). The mixture is stirred at 60 to 90° C.(preferably, approximately 70° C.) for 1 to 10 hours (preferably,approximately 4 hours). The solvent is removed under reduced pressure,and the residue was filtered off and washed with an appropriate organicsolvent (e.g., ether, ethylacetate, n-hexane) to give the objective, acompound (IV-3).

A condensing agent such as DCC, EDC or the like can be used in acoupling reaction of carboxylic acid and alcohol.

Another method of an esterifing reaction includes a method reacting withhalogenated alkyl (e.g., methyl iodide, ethylbromide) in the presence ofa base, a method reacting with diazomethane or trimethyiscilyldiazomethane, a method reacting with alkene (e.g., isobutylene) or thelike.

wherein R⁵ is hydrogen or optionally substituted alkyl, R⁶ is hydrogen,optionally substituted alkyl or optionally substituted aryl.

This scheme shows a process for the preparation of a compound (IV-4),which comprises a cyclization of a compound (V). In the past, thisprocess should be performed at a high temperature (over melting point ofa compound (V). This process can be performed by using the presentinvention at lower temperature, suitable to industrial production.

This process includes two kinds of methods, as shown below.

1) A Method Performed in the Presence of trialkylorthoester.

To a compound (V) are added trialkylorthoester (e.g., triethylorthoformate, trimethyl orthoformate, triethyl orthoacetic acid,trimethyl orthoacetic acid, triethyl orthobenzoic acid, trimethylorthobenzoic acid, triethyl orthoproprionic acid, trimethylorthoproprionic acid) and an organic solvent (e.g., benzene, toluene,xylene). The mixture is stirred at 100 to 130° C. (preferably, 110 to120° C.) for 1 to 10 hours (preferably, approximately 2.5 hours). Aby-product, alcohol (produced from trialkylortho ester) is removed undera usual pressure. The distilled product is cooled at 0 to 20° C.(preferably, under 10° C.) and allowed to stand for 0.5 to 10 hours(preferably, approximately 1 hour). The objective, a compound (IV-4) canbe obtained by filtering the precipitated crystal.

2) A Method Performed in the Presence of an Acid Catalyst.

To a compound (V) are added a catalytic amount (0.01-0.5, preferably,approximately 0.1 mole equivalent to a compound (V)) of an acid (e.g.,methane sulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid,p-toluenesulfonic acid mono hydrate, hydrochloric acid, sulfuric acid,nitric acid, polyphosphoric acid) and an organic solvent (e.g.,dimethylformamide, N-methylpyrrolidone). The mixture is stirred at 100to 130° C. (preferably, 110 to 120° C.) for 1 to 10 hours (preferably,approximately 3 hours). The reaction mixture is cooled at 0 to 20° C.(preferably, under 10° C.), mixed with an organic solvent (e.g.,benzene, toluene, xylene) and stirred under cooling for 0.5 to 10 hours(preferably, approximately 1.5 hours). The objective, a compound (IV-4)can be obtained by a filtration of the precipitated crystal.

A compound (V) can be prepared by reacting thioformimidate withacylhydrazine (Collect. Czech. Chem. Commun., 49, 1984, 2492-2495, J.Heterocyclic Chem., 25, 651-654, 1998) as well as by reactingformimidate with acyl hydrazine.

A compound (V) includes ethyl β formyl oxalylamidrazone (a compoundwherein R⁵ is ethyl; and R⁶ is hydrogen), methyl β formyloxalylamidrazone (a compound wherein R⁵ is methyl; and R⁶ is hydrogen),ethyl β acetyloxalylamidrazone (a compound wherein R⁵ is ethyl; and R⁶is methyl), methyl β acetyloxalylamidrazone (a compound wherein R⁵ ismethyl; and R⁶ is methyl), ethyl β propionyloxalylamidrazone (a compoundwherein R⁵ is ethyl; and R⁶ is ethyl), methyl βpropionyloxalylamidrazone (a compound wherein R⁵ is methyl; and R⁶ isethyl), β formyl oxalylamidrazone (a compound wherein R⁵ and R⁶ each ishydrogen), β acetyloxalylamidrazone (a compound wherein R⁵ is hydrogen;and R⁶ is methyl), β propionyloxalylamidrazone (a compound wherein R⁵ ishydrogen; and R⁶ is ethyl) or the like. Preferred is a compound whereinR⁵ is alkyl, especially, ethyl β formyl oxalylamidrazone (a compoundwherein R⁵ is ethyl; and R⁶ is hydrogen) or methyl β formyloxalylamidrazone (a compound wherein R⁵ is methyl; and R⁶ is hydrogen).

wherein R⁵ is optionally substituted alkyl; R⁶ is hydrogen, optionallysubstituted alkyl or optionally substituted aryl; R¹² is a group of theformula: —R⁷ wherein R⁷ is trityl, optionally substituted sulfamoyl oroptionally substituted alkoxymethyl, a group of the formula:—C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is optionally substituted alkyl; R⁹, R¹⁰and R¹¹ each is independently hydrogen or optionally substituted alkyl;or R⁸ and R¹⁰ may be taken together to form optionally substitutedalkylene, or hydroxy methyl.

This process includes a process for the preparation of a compound (IV-6)which comprises introducing a protecting group (R¹²) to a compound,(IV-5).

To a compound (IV-5) was added an organic solvent (e.g.,tetrahydrofuran, dimethylformamide). To a compound (IV-5) is added oneor more mole equivalent, preferably approximately 1.25 mole equivalentof a compound of the formula: R⁷X wherein R⁷ is trityl, optionallysubstituted sulfamoyl or optionally substituted alkoxy methyl; and X ishalogen, to a compound (IV-5), if desired, in the presence of one ormore mole equivalent, preferably approximately 1.1 mole equivalent of abase (e.g., sodium hydride, N,N-dimethylacetamide) to a compound (IV-5).In another method, to a compound (IV-5) is added one or more moleequivalent, preferably approximately 1.1 mole equivalent of a compoundof the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸ is optionally substitutedalkyl; R⁹, R¹⁰ and R¹¹ each is independently hydrogen or optionallysubstituted alkyl; or R⁸ and R¹⁰ may be taken together to formoptionally substituted alkylene to a compound (IV-5) in the presence of0.01-0.5 mole equivalent, preferably approximately 0.03 mole equivalentof an acid (e.g., methane sulfonic acid, benzene sulfonic acid,p-toluenesulfonic acid, p-toluenesulfonic acid mono hydrate,hydrochloric acid, sulfuric acid, nitric acid) to a compound (IV-5).

The reaction mixture is stirred for 0.5 to 10 hours, preferablyapproximately 2 hours at room temperature, if desired, under heating.The mixture is extracted, washed, removed under reduced pressure andfiltered to give the objective compound (IV-6).

When introducing tetrahydropyran-2-yl as a protecting group, a compound(IV-5) can be reacted with 3,4-dihydro-2H-pyran in the presence of anacid in THF. The acid can be used equivalent to a compound (IV-5) or ina catalytic amount. The acid includes p-toluene sulfonic acid, benzenesulfonic acid or the like.

When introducing 1-methoxy-1-methylethyl as a protecting group, acompound can be reacted with 2-methoxypropene in the presence of an acidin THF. The acid can be used equivalent to a compound (IV-5) or in acatalytic amount. The acid includes p-toluene sulfonic acid, benzenesulfonic acid or the like.

A compound of the formula: R⁷X includes tritylchloride, tritylbromide,methoxymethylchloride, methoxymethylbromide, ethoxymethylchloride,ethoxymethylbromide, sulfamoyl chloride, N,N-dimethylsulfamoyl chloride,sulfamoyl bromide, N,N-dimethylsulfamoyl bromide or the like.

A compound of the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ includes3,4-dihydro-2H-pyran (a compound wherein R⁸ and R¹⁰ are taken togetherto form trimethylene; and R⁹ and R¹¹ each is hydrogen),2-methoxypropenone (a compound wherein R⁵ and R⁹ each is methyl; and R¹⁰and R¹¹ each is hydrogen), 2-ethoxypropene (a compound wherein R⁸ isethyl; R⁹ is methyl; and R¹⁰ and R¹¹ each is hydrogen), methylvinylether (a compound wherein R⁸ is methyl; and R⁹, R¹⁰ and R¹¹ each ishydrogen), ethylvinyl ether (a compound wherein R⁸ is ethyl; and R⁹, R¹⁰and R¹¹ each is hydrogen), n-propylvinyl ether (a compound wherein R⁸ isn-propyl; and R⁹, R¹⁰ and R¹¹ each is hydrogen), n-butylvinyl ether (acompound wherein R⁸ is n-butyl; and R⁹, R¹⁰ and R¹¹ each is hydrogen),isobutylvinyl ether (a compound wherein R⁸ is isobutyl; and R⁹, R¹⁰ andR¹¹ each is hydrogen) or the like.

Besides the above process, a hydroxymethyl group can be introduced as aprotecting group to a compound (IV-5) by reacting with formaldehyde inaccordance with a method described in A. R. Katritzky and K. Akutagawa,J. Org. Chem., 54, 2929 (1989).

wherein R⁶ is hydrogen, optionally substituted alkyl or optionallysubstituted aryl; and R¹² is a group of the formula: —R⁷ wherein R⁷ istrityl, optionally substituted sulfamoyl or optionally substitutedalkoxy methyl, a group of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ isoptionally substituted alkyl; R⁹, R¹⁰ and R¹¹ each is independentlyhydrogen or optionally substituted alkyl; or R⁸ and R¹⁰ may be takentogether to form optionally substituted alkylene, or hydroxy group.

This process includes a process for the preparation of a compound VI-8)which comprises introducing protective groups (R¹²) at two positions toa compound (IV-7). The introduction of a protecting group at twopositions at the same time can reduce the number of steps, thus beingefficient and useful for industrial production.

This step can be carried out as well as the above B-4) except doublingthe amount of a base and a compound of the formula: R⁷X, an acid and acompound of the formula:

(R⁸O)R⁹C═CR¹⁰R¹¹,

or formaldehyde.

A process for the preparation of substituted propenone derivatives isexplained below.

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; A is CR⁶ orN; R⁶ is hydrogen, optionally substituted alkyl or optionallysubstituted aryl; L is a leaving group; and Q is a protecting group.

This scheme shows a process for the preparation of1-[5-benzylfuran-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonederivatives from 2-acetyl-5-benzylfuran derivatives. This step can becarried out in the presence of a base, and followed by deprotection of aprotecting group (Q) on tetrazolyl or triazolyl. In this step, acompound (III-2), a compound (III-1) wherein R³ is methyl can be used.

A compound of the formula (III-2) includes 2-acetyl-5-benzylfuran,2-acetyl-5-(4-methylbenzyl)furan, 2-acetyl-5-(4-methoxybenzyl)furan,2-acetyl-5-(4-fluorobenzyl)furan, 2-acetyl-5-(4-chlorobenzyl)furan,2-acetyl-5-(3-methylbenzyl)furan, 2-acetyl-5-(3-methoxybenzyl)furan,2-acetyl-5-(3-fluorobenzyl)furan, 2-acetyl-5-(3-chlorobenzyl)furan orthe like. Preferred is 2-acetyl-5-(4-fluorobenzyl)furan.

A compound of the formula (IV-10) includes2-trityl-2H-tetrazole-5-carboxylic acid ethyl ester,1-trityl-H-1,2,4-triazole-3-carboxylic acid methyl ester,1-trityl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester or the like.Preferred is 1-trityl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester,1-trityl-1H-1,2,4-triazole-3-carboxylic acid methyl ester.

A protecting group (Q) includes methoxymethyl, dialkoxy methyl,tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, tosyl, trityl, allyl,formyl or the like. Moreover, a protecting group includes a group of theformula: —R⁷ wherein R⁷ is trityl, optionally substituted sulfamoyl oroptionally substituted alkoxymethyl, a group of the formula:—C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is optionally substituted alkyl; R⁹, R¹⁰and R¹¹ each is independently hydrogen or optionally substituted alkyl;or R⁸ and R¹⁰ may be taken together to form optionally substitutedalkylene, or hydroxy methyl. A deprotection of these protecting groupscan be carried out, depending on the kind of protecting groups. Thedeprotection can be carried out by hydrolysis under an acidic conditionor a basic condition.

A leaving group (L) includes alkoxy (methoxy, ethoxy, isopropoxy,tert-butoxy, biphenylmethoxy), heteroaryl (imidazolyl, tetrazolyl),cyano or the like. Preferred is methoxy or ethoxy.

A base includes sodium methoxide, sodium ethoxide, potassiumtert-butoxide, n-butyllithium, lithiumbistrimethylscilylamide or thelike. Preferred is sodium methoxide.

A reaction solvent includes dimethylformamide, tetrahydrofuran, dioxane,alcohols (e.g., methanol, ethanol, isopropylalcohol) or the like. Amixed solvent can be used as a reaction solvent. Preferred istetrahydrofuran, methanol or a mixed solvent thereof.

A reaction temperature is −100 to 100° C., preferably −50 to 50° C.

A reaction time is 1 to 48 hours, preferably 1 to 24 hours.

A compound of the formula (III-2), a compound of the formula (IV-10) anda base can be added in any order. For example, a base may be added to acompound of the formula (III-2), and after a couple of minutes or hoursa compound of the formula (IV-10) may be added thereto. As anothermethod, abase (or a solvent comprising a base) may be added dropwise toa mixture of a compound of the formula (III-2) and a compound of theformula (IV-10).

Preferred is a process described in the following C2.

wherein R¹, R², and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; R⁶ ishydrogen, optionally substituted alkyl or optionally substituted aryl;R¹³ is optionally substituted alkyl, a group of the formula: —R⁷ whereinR⁷ is trityl, optionally substituted sulfamoyl or optionally substitutedalkoxymethyl, a group of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ isoptionally substituted alkyl; R⁹, R¹⁰ and R¹¹ each is independentlyhydrogen or optionally substituted alkyl; or R⁸ and R¹⁰ may be takentogether to form optionally substituted alkylene, or hydroxymethyl; andR¹⁴ is a group of the formula —R⁷ wherein R⁷ is as defined above, agroup of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ areas defied above, or hydroxymethyl.

This scheme shows a process for the preparation of a compound of theformula (VI-2) which comprises reacting a compound of the formula (IV-9)obtained in process B4 or B5 with a compound of the formula (III-2) inthe presence of a base and deprotecting R¹⁴ on triazole.

A compound of the formula (III-2), a base, a reaction solvent, areaction temperature and a reaction time are the same as Process C1.

A preferred compound of the formula (IV-9) includes a compound of theformula (IV-9):

wherein R⁶ is hydrogen or alkyl; R¹³ is alkyl, a group of the formula:—R⁷ wherein R⁷ is trityl, optionally substituted sulfamoyl or alkoxymethyl, a group of the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is alkylR⁹, R¹⁰ and R¹¹ each is independently hydrogen or alkyl; or R⁸ and R¹⁰may be taken together to form alkylene, or hydroxymethyl; and R¹⁴ is agroup of the formula: —R⁷ wherein R⁷ is as defined above, a group of theformula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ are defiedabove, or hydroxymethyl; provided that a compound wherein R⁶ ishydrogen; R¹³ is methyl; and R¹⁴ is trityl, a compound wherein R⁶ ishydrogen; R¹³ is methyl; and R¹⁴ is tetrahydropyran-2-yl and a compoundwherein R⁶ is hydrogen; R¹³ is ethyl; and R¹⁴ is trityl are excluded.More Preferred is a compound wherein R⁶ is hydrogen; R¹³ is methyl orethyl; and R¹⁴ is tetrahydropyran-2-yl, hydroxymethyl, methoxymethyl,ethoxymethyl, N,N-dimethylsulfamoyl, (1-methoxy-1-methyl)ethyl,(1-ethoxy)ethyl, (1-ethoxy-1-methyl)ethyl, (1-n-propoxy)ethyl,(1-n-butoxy)ethyl or (1-isobutoxy)ethyl.

For example, a compound of the formula (IV-9) includes1-trityl-1H-1,2,4-triazole-3-carboxylic acid methyl ester,1-trityl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester,1-(tetrahydropyran-2-yl)-1H-1,2,4-triazole-3-carboxylic acid ethylester, 1-hydroxy methyl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester,1-methoxymethyl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester,1-[(1-methoxy-1-methyl)ethyl]-1H-1,2,4-triazole-3-carboxylic acid ethylester, 1-[(1-ethoxy)ethyl]1H-1,2,4-triazole-3-carboxylic acid ethylester, 1-[(1-ethoxy-1-methyl)ethyl]-1H-1,2,4-triazole-3carboxylic acidethyl ester, 1-[(1-n-propoxy)ethyl]-1H-1,2,4-triazole-3-carboxylic acidethyl ester, 1-[(1-n-butoxy)ethyl]-1H-1,2,4-triazole-3-carboxylic acidethyl ester, 1-trityl-1H-1,2,4-triazole-3-carboxylic acid methyl ester,1-(tetrahydropyran-2-yl)-1H-1,2,4-triazole-3-carboxylic acid methylester, 1-hydroxy methyl-1H-1,2,4-triazole-3-carboxylic acid methylester,1-methoxymethyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester,1-[(1-methoxy-1-methyl)ethyl]-1H-1,2,4-triazole-3-carboxylic acid methylester, 1-[(1-ethoxy)ethyl]-1H-1,2,4-triazole-3-carboxylic acid methylester, 1-[(1-ethoxy-1-methyl)ethyl]-1H-1,2,4-triazole-3-carboxylic acidmethyl ester, 1-[(1-n-propoxy)ethyl]-1H-1,2,4-triazole-3-carboxylic acidmethyl ester, 1-[(1-n-butoxy)ethyl]-1H-1,2,4-triazole-3-carboxylic acidmethyl ester or the like.

This process can be carried out as shown below. In an organic solvent(e.g., tetrahydrofuran, dioxane, diethylether) is dissolved a compoundof the formula (III-2). 1.0 to 3.0 mole equivalent, preferablyapproximately 2 mole equivalent of a base described above to a compoundof the formula (III-2) is added thereto at −80 to −10° C., preferably−30 to −25° C. The mixture is stirred at the same temperature for 1 to10 hours, preferably approximately 1.5 hours. A solution of a compoundof the formula (IV-9) in an organic solvent (e.g., tetrahydrofuran,dioxane, diethyl ether) is added thereto at −80 to −5° C. (preferably,−32 to −7° C.). The mixture is warmed up to the room temperature(approximately 25° C.) and stirred for 1 to 10 hours (approximately 2hours). After that, the reaction mixture is poured into an acid (e.g.,dilute hydrochloric acid) for neutralizing excess of a base, extractedwith an organic solvent (e.g., methylene chloride, chloroform,ethylacetate), washed with water, concentrated under reduced pressureand filtered to give a crystal.

A protected derivative includes a compound of the formula (IV-7):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; R⁶ ishydrogen, optionally substituted alkyl or optionally substituted aryl;and R¹⁴ is a group of the formula: —R⁷ wherein R⁷ is trityl, optionallysubstituted sulfamoyl or optionally substituted alkoxy methyl, a groupof the formula: —C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is alkyl; R⁹, R¹⁰ and R¹¹each is independently hydrogen or optionally substituted alkyl; or R⁸and R¹⁰ may be taken together to form alkylene, or hydroxymethyl.Preferred is a compound wherein R⁴ is 4-fluoro; R¹, R² and R⁶ each ishydrogen; and R¹⁴ is trityl, tetrahydropyran-2-yl, hydroxymethyl,methoxymethyl, ethoxymethyl, N,N-dimethylsulfamoyl,(1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl, (1-ethoxy-1-methyl)ethyl,(1-n-propoxy)ethyl, (1-n-butoxy)ethyl or (1-isobutoxy)ethyl.

To a suspension of a crystal in an organic solvent (e.g., ethanol,dioxane) is added for removing a protecting group (R¹⁴ on triazole)0.01-10.0 mole equivalent, preferably 0.1-5.0 mole equivalent of an acid(e.g., hydrochloric acid, sulfuric acid, nitric acid) or a base (e.g.,potassium carbonate, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, sodium carbonate, sodium methoxide, sodium ethoxide)to a compound of the formula (III-2). The mixture is stirred at 0 to100° C. (preferably 20 to 70° C.) for 1 to 10 hours (e.g., approximately1 hour). An acid or a base can be used as a catalyst, which depends on akind of protecting groups. When 1-methoxy-1-methylethyl group is used asa protecting group, it can be removed by using a catalytic amount ofsulfuric acid.

When a base is used as a deprotecting agent, the objective compound ofthe formula (VI-2) can be obtained by cooling the reaction mixture andfiltering the precipitated crystal.

When an acid is used as a deprotecting agent, a compound of the formula(VI-2) forms a salt with an acid. Therefore, the objective compound ofthe formula (VI-2) can be obtained by cooling the reaction mixture,adding 1.0-4.0 mole equivalent, preferably approximately 3.0 moleequivalent of a base (e.g., sodium hydroxide, potassium hydroxide,sodium carbonate, sodium hydrogencarbonate) for neutralizing excess ofan acid to form a acid-free crystal, and filtering the precipitatedcrystal.

Impurities or the like can be removed by isolating a crystal as a salt.The obtained salt can be changed to a free form by adding a basicaqueous solution or the like after drying or without drying.

The obtained salt can be changed to a free form by adding to an aqueoussolution or THF containing water without neutralizing it with a base,which depends on a kind of acids.

Preferred as a salt is a salt with hydrochloride or the like.

The obtained propenone derivatives can form keto-enol isomers orcis-trans isomers as shown below. In a solution, these isomers are atthe equilibrium. Each isomer can be isolated as a crystal by selecting acrystallizing condition (e.g., crystallizing solvent, crystallizingtemperature, time).

wherein A is CR⁶ or N; R⁶ is hydrogen, optionally substituted alkyl oroptionally substituted aryl; and R¹, R² and R⁴ each is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkoxy orhalogen.

In the present specification, a compound of the formula (VI-1) includesall of the above isomers. On the other hand, an isomer having astructure of the formula (VI-1) means an isomer having a specificstructure represented by the formula (VI-1).

When a compound of the formula (VI-1) is1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone(a compound of the formula (VI-1) wherein R¹ and R² each is hydrogen; R⁴is p-fluoro; and A is CH), the following three crystals (type I, type IIand type III) can be obtained.

A Crystal (Type I)

It is determined by single crystal X-ray diffraction that a crystal(type I) is an isomer having a structure of the formula (VI-1). Acrystal (type I) can be obtained by generally known crystallizingmethods. For example, a crystal (type I) can be obtained by dissolving acompound of the formula (VI-1) in a warmed organic solvent, removingimpurities by a plaited filter paper and cooling the solution. Anyorganic solvent, as far as a compound of the formula (VI-1) can bedissolved, can be used, for example, an organic solvent such astetrahydrofuran, dimethylformamide, ethanol, methanol, isopropanol,ether, isopropylether, ethylacetate, methylene chloride, chloroform,dioxane or the like, a mixed solvent thereof (e.g.,tetrahydrofuran/ethanol) or a solvent containing water (e.g.,tetrahydrofuran/water). Considering a crystallizing yield or the like,preferred is an organic solvent, the solubility thereto much depends ontemperature.

A crystal (Type II)

It is determined by single crystal X-ray diffraction that a crystal(type II) is an isomer having a structure of the formula (VI-4). Acrystal (type II) can be obtained by dissolving a compound of theformula (VI-1) in an organic solvent at a lower concentration than thatfor obtaining a crystal (type I) and keeping it for several hours toseveral days. Preferred as an organic solvent for obtaining a crystal(type II) is an organic solvent which can gradually be vaporized even atroom temperature (e.g., ethylacetate). A crystal (type II) can beprecipitated by dissolving a compound of the formula (VI-1) in anorganic solvent and naturally vaporizing the solvent at room temperaturefor several hours or several days.

A Crystal (type III)

It is determined by powder X-ray diffraction, infrared absorptionspectrum and diffrential scanning calorimetry that this crystal isdifferent from the above crystal (type I) and (type II). A crystal (typeIII) can be obtained by adding an alcohol (e.g., methanol, ethanol) orthe like to a hydrochloride of a compound of the formula (VI-1) underheating and stirring, concentrating the alcohol under reduced pressure,adding an alcohol, repeating the same steps and filtering theprecipitated crystal.

These crystals (type I), (type II) and (type III) are at the equilibriumin vivo and have anti-HIV activities. Therefore, all crystals are usefulas anti-HIV agents.

Among these crystals (type I), (type II) and (type III), preferred is acrystal (type I), because it can easily be prepared and stably beprovided.

These crystals can be identified by single crystal X-ray diffraction,powder X-ray diffraction, infrared absorption spectrum and diffrentialscanning calorimetry. Each crystal can be identified by theseinstrumental analysis.

A crystalline substance can be identified by crystal parameter of singlecrystal X-ray diffraction such as unit cell constants and its spacegroup. Unit cell constants are represented by lengths of its side faces,relative angles between its side faces and volume of itself. The lengthsof its side faces are represented by a, b and c. The relative anglesbetween its side faces are determined by α, β and γ. The volume ofitself is determined by V. A unit cell is precisely explained in X-RayStructure Determination; A Practical Guide, Macmirian, Staut and Jensen,New York (1968). Single crystal X-ray diffraction can be performed underthe condition of CuKa, 1.54 Å (monochrometer), voltage 60 kV andelectricity 300 mA. A measuring data includes experimental errors. Forexample, a data that a=32.432(2) Å means that a=32.432±0.002 Å, andgenerally includes that a=32.432±0.002×3 Å. Even if such experimentalerrors are put under consideration, characteristic peaks of singlecrystal X-ray diffraction of the above crystals are different from eachother. Therefore, each crystal can be identified.

In powder X-ray diffraction, measuring peaks may include more or lessexperimental errors, which depend on a measuring equipment or measuringcondition. For example, a data of a diffraction angle (2θ) may includeexperimental errors of approximately ±0.2, and even if using veryprecise equipment, may include experimental errors of approximately±0.1. Therefore, experimental errors can be considered for identifyingeach crystal. Even if such experimental errors are taken intoconsideration, characteristic peaks of powder X-ray diffraction of theabove crystals are different from each other. Therefore, each crystalcan easily be identified. Powder X-ray diffraction can be performedunder the condition of CuKα, 1.54 Å (monochrometer), voltage 40 kV andelectricity 40 mA.

Each crystal can be identified by its characteristic absorption band ofan infrared absorption spectrum. The absorption band may include a fewexperimental errors, which depend on measuring assemblies, measuringconditions and measuring methods such as a film method, a solutionmethod, a nujol mull method and a KBr method. In a solution method, theabsorption band may include a few experimental errors, which depend on asolvent to be used (e.g., CCl₄, CS₂, CHCCl₃, CH₂CL₂). When the structureof each crystal is identified, an experimental error should beconsidered. Even if an experimental error is considered, eachcharacteristic absorption band and fingerprint region of each crystalare different form each other. Therefore, each crystal can beidentified.

In diffrential scanning calorimetry, each crystal has its owncharacteristic peaks. These characteristic peaks can be determined bythe obtained measuring charts. Each crystal can be identified by peaks(melting points) or change of energy of mass unit of a sample (ΔH).Approximately 1 to 3 mg of a sample is used for measuring. A scanningspeed is 10.0° C./min. A measuring can be preformed between 25.0 to 200°C.

EXAMPLE

Examples of the above processes A to C are shown below. The scope of thepresent invention should not be limited to these examples.

Example 1 A process for the Preparation of2-acetyl-5-(4-fluorobenzyl)furan

Example 1(1) Example of Using Methylene Chloride as a Reaction Solvent

To a solution of 19.71 g (0.18 mol) of 2-acetylfuran in 120 ml ofmethylene chloride were added 42.9 ml (2.0 eq) of 4-fluorobenzylchlorideand 36.6 g (1.5 eq) of zinc chloride. The mixture was refluxed for 12hours. The precipitated crystal was filtered and washed with methylenechloride. The obtained solid was dissolved in water and extracted withethylacetate. The organic layer was washed with water and a dilutedaqueous solution of sodium hydrogencarbonate and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas recrystallized from n-hexane to give 16.4 g of2-acetyl-5-(4-fluorobenzyl)furan. Yield: 42%. Mp: 27-29° C.

¹H NMR δ (CDCl₃): 2.43 (s, 3H), 4.01 (s, 2H), 6.09 (d, J=3.5 Hz, 1H),6.96-7.26 (m, 5H).

Example 1(2) Example Without a Reaction Solvent

A mixture of 9.2 g (83.4 mmol) of 2-acetylfuran, 20 ml (2.0 eq) of4-fluorobenzylchloride and 22.8 g (2.0 eq) of zinc chloride were stirredat 25° C. for 20 hours. The stirring gradually became difficult due tothe precipitate. The mixture was dissolved in water and extracted withethylacetate. The organic layer was washed with water and a dilutedsodium hydrogencarbonate aqueous solution and dried over sodium sulfate.The solvent was removed under deduced pressure. A fractionaldistillation under reduced pressure of the residue gave 9.6 g of2-acetyl-5-(4-fluorobenzyl)furan. Yield: 53%. 2 mmHg/120-125° C.

Example 1(3) Example of Using Water as a Reaction Solvent

To 258 g (0.94 mol) of a 50% aqueous solution of zinc chloride wereadded 69.3 g of water, 99.0 g (0.90 mol) of 2-acetylfuran and 260 g(1.80 mol) of 4-fluorobenzylchloride. The mixture was stirred at 85° C.for 6 hours. The reaction mixture was cooled and extracted withethylacetate. The extract was washed with 1N hydrochloric acid, washedwith an aqueous sodium hydrogencarbonate solution and removed underreduced pressure. The obtained residue was distilled under reducedpressure to give 145.4 g of crude 2-acetyl-5-(4-fluorobenzyl)furan(106-121° C./0.4 mmHg). The crude product was recrystallized fromisopropylalcohol/n-hexane to give 84.4 g of2-acetyl-5-(4-fluorobenzyl)furan. Yield: 43%.

Example 2 A process for the Preparation of1H-1,2,4-triazole-3-carboxylic acid

Example 2(1) Example of Adding Diluted Hydrochloric Acid

To 2.74 g (20 mmol) of 3-amino-1,2,4-triazole-5-carboxylic acid wereadded 12 g of 6% diluted hydrochloric acid, 12.7 g of 13.5% aqueoushypophosphorous acid solution and 0.2 ml of isopropylalcohol. Themixture was warmed at 42° C. To the suspension was added, at 42 to 50°C. for approximately 25 minutes under stirring, 5.2 ml of an aqueoussolution of 1.52 g (22 mmol) of sodium nitrite. After addition, themixture was stirred at the same temperature for 30 minutes. The reactionmixture was cooled at approximately 5° C. and stirred for 30 minutes.The obtained suspension was filtered and washed with 15 ml of ice water.The obtained crystal was heated at 40° C. under reduced pressure to give2.02 g of 1H-1,2,4-triazole-3-carboxylic acid. Yield: 89.4%.

Mp: 146-149° C.

¹H NMR(d6-DMSO) δ 8.53(s, 3H).

Example 2(2) When a Diluted Hydrochloric Acid is not Added

To 2.74 g (20 mmol) of 3-amino-1,2,4-triazole-5-carboxylic acid wereadded 12.7 g of a 13.5% aqueous solution of hypophosphorous acid and 0.3ml of isopropylalcohol. The mixture was warmed at 45° C. To thesuspension was added, at 45 to 50° C. for 25 minutes under stirring, 5.2ml of an aqueous solution of 1.52 g (22 mmol) of sodium nitrite. Afteraddition, the mixture was stirred at the same temperature for 30minutes. The mixture was cooled at approximately 5° C. for 30 minutes.The obtained suspension was filtered and washed with 15 ml of ice water.The obtained crystal was dried with heating at 40° C. under reducedpressure to give 2.16 g of 1H-1,2,4-triazole-3-carboxylic acid (2).Yield: 95.6%.

Mp: 145-150° C.

Example 3 A Process for the Preparation of1H-1,2,4-triazole-3-carboxylic acid ethyl ester hydrochloride

To 10 ml of a solution of 1.00 g (8.85 mmol) of1H-1,2,4-triazole-3-carboxylic acid in 99.5% ethanol was added dropwiseunder stirring and cooling at 5° C. 1.58 g (13.2 mmol) ofthionylchloride. The mixture was stirred under heating at 70° C. for 4hours. Then, the solvent was removed under reduced pressure and theobtained residue was washed with 18 ml of ethylacetate. The obtainedcrystal was dried at room temperature under reduced pressure to give1.00 g of 1H-1,2,4-triazole-3-carboxylic acid ethyl ester hydrochloride.Yield: 63.7%.

Mp: 115-120° C.

¹H NMR(d6-DMSO) δ 1.26(t, 3H, J=7.2 Hz) 4.28(q, 2H, J=7.2 Hz) 8.61(s,1H); 9.19(s, 2H).

¹³C NMR(d6-DMSO) δ 14.0, 60.8, 142.8, 145.6, 159.09.

Example 4 A Process for the Preparation of ethyl β-formyl oxalamidrazone

To a solution of 64.1 g (1.76 mol) of hydrogen chloride in 874 ml ofethylacetate was added 103 ml of anhydrous ethanol. The mixture wascooled at 5° C. 145 g (1.46 mol) of ethylcyanoformate was added theretounder stirring at 5-9° C. for approximately 10 minutes. After addition,the mixture was stirred at 0 to 10° C. for approximately 20 hours. Tothe reaction mixture was added under 10° C. 580 ml of methanol and theprecipitated crystal of formimidate was dissolved therein. The solutionwas added dropwise under 10° C. for approximately 20 minutes to asolution of formylhydrazine in methanol (prepared from 872 ml ofmethanol, 73 g (1.46 mol) of hydrazine monohydrate and 119.2 g (1.6 mol)of ethylformate ester). After addition, the mixture was stirred at 5 to10° C. for 1 hour. 702.4 g of a 10% aqueous solution of sodium hydroxidewas added dropwise thereto at the same temperature for approximately 30minutes to make the pH of the reaction solution pH 7. The neutralizedsolution was heated at 45° C. under reduced pressure and approximately1850 ml of methanol was removed. The obtained residue was stirred at 5°C. for 1 hour and a crystal was precipitated. The precipitated crystalwas filtered, washed with 244 ml of ice water and dried with beating at40° C. under reduced pressure to give 130.97 g of ethyl β formyloxalamidrazone. Yield: 56.2%.

Example 5 A Process for the Preparation of1H-1,2,4-triazole-3-carboxylic acid ethyl ester

Example 5(1) In the Presence of ortho triethylformate

To 130.97 g (0.82 mol) of ethyl β formyl oxalamidrazone were added 243.9g (1.64 mol) of ortho triethylformate and 1310 ml of toluene. Themixture was refluxed at oil bath (110-120° C.) for 2.5 hours. Afterthat, a side product, ethanol was removed approximately 200 g underusual pressure before the temperature of the mixture becameapproximately 100° C. The concentrated solution was cooled and thecrystal was precipitated at 5-10° C. for 1 hour. The precipitatedcrystal was filtered, washed with 249 ml of iced toluene and dried withheating at 45° C. under reduced pressure to give 112 g of1H-1,2,4-triazole-3-carboxylic acid ethyl ester. Yield: 96.8%.

Mp: 180-182° C.

¹H NMR(CDCl₃) δ 1.30(t, 3H, J=6.9 Hz) 4.22(q, 2H, J=6.9 Hz) 8.66(s, 1H).

Example 5(2) Example in the Presence of p-toluenesulfonic acid

A mixture of 500 mg (3.42 mmol) of ethyl β formyl oxalamidrazone, 60 mg(0.32 mmol) of p-toluenesulfonic acid monohydrate and 1 ml of DMF werestirred with heating at 120° C. for 3 hours. The mixture was cooled atroom temperature. 10 ml of toluene was added thereto and stirred underice cooling for 1.5 hours. The precipitated crystal was filtered, washedwith 9 ml of iced toluene and dried with heating 45° C. under reducedpressure to give 389 mg of 1H-1,2,4-triazole-3-carboxylic acid ethylester. Yield: 87.8%.

Example 6 A Process for the Preparation of1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxylic acid ethyl ester

Example 6(1) Example of Using p-toluenesulfonic acid

To a suspension of 1.25 g (8.86 mmol) of 1H-1,2,4-triazole-3-carboxylicacid ethyl ester in 4 ml of THF was added 51 mg (0.27 mmol) ofp-toluenesulfonic acid monohydrate. To the suspension was added at roomtemperature with stirring 1 ml (11 mmol) of 3,4-dihydro-2H-pyran. Themixture was stirred at room temperature for 2 hours and extracted with15 ml of ethylacetate. The extract was washed with a saturated aqueoussolution of sodium hydrogencarbonate and dried over Na₂SO₄. The solventwas concentrated under reduced pressure to give 1.98 g of an oil. Theobtained oil was purified with silica gel chromatography (eluate:ethylacetate) to give 1.81 g of1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxylic acid ethyl ester ascolorless oil. Yield: 91%.

NMR(CDCl₃) δ 1.43(t, 3H, J=7.2 Hz) 1.66-1.74(m, 3H) 2.01-2.05(m, 2H)2.21-2.25(m, 1H) 3.72-3.77(m, 1H) 4.07-4.11(m, 1H) 4.48(q, 2H, J=7.2 Hz)5.54(dd, 1H, J=2.7, 9.0 Hz) 8.37(s, 1H).

IR(neat) 1738 cm³¹ ¹.

Example 6(2) Example of Using benzene sulfonic acid

1-(Tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxylic acid ethyl esterwas obtained by using a catalytic amount of benzene sulfonic acid inplace of p-toluenesulfonic acid monohydrate in Example 6(1).

Example 7 A Process for the Preparation of1-trityl-1,2,4-triazole-3-carboxylic acid ethyl ester

In 60 ml of DMF was dissolved 7.62 g (54 mmol) of1H-1,2,4-triazole-3-carboxylic acid ethyl ester. To the solution wereadded at room temperature 14 g (108 mmol) of N,N-diisopropylethylamineand 15.8 g (56.7 mmol) of tritylchloride. The mixture was stirred for 2hours. 300 ml of water and 300 ml of ethylacetate were added thereto.The crystal was filtered, dissolved in 150 ml of chloroform, washed withwater and dried. The solvent was removed. The residue was crystallizedfrom ether to give 8.91 g of the titled compound. The ethylacetate layerwas washed with water, dried and evaporated. The residue wascrystallized from ether to give 4.73 g of the titled compound. 13.64 gof 1-trityl-1,2,4-triazole-3-carboxylic acid ethyl ester was totallyobtained. Yield: 66%.

NMR(CDCl3) δ: 1.41(3H, t, J=7.2 Hz), 4.45(2H, q, J=7.2 Hz),7.11-7.13(6H, m), 7.32-7.36, 8.01(1H, s).

Example 8 Process for the Preparation of1-(N,N-dimethylsulfamoyl)-1,2,4-triazole-3-carboxylic acid ethyl ester

To a solution of 1.02 g (7.23 mmol) of 1H-1,2,4-triazole-3-carboxylicacid ethyl ester in 6 ml of DMF was added 1.46 g (1.44 mmol) oftriethylamine. To the solution was added dropwise with stirring underice-cooling 1.14 g (7.94 mmol) of dimethylsulfamoyl chloride. Themixture was stirred at room temperature for 8 hours. 30 ml of Water wasadded thereto and extracted with 20 ml of ethylacetate. The extract waswashed with a saturated aqueous solution of sodium hydrogencarbonate andwater, dried over Na2SO₄ and evaporated under reduced pressure to givean oil. The obtained oil was purified with silica gel chromatography(eluate: hexane/ethylacetate=2:1) to give 1.46 g of1-dimethylsulfamoyl-1,2,4-triazole-3-carboxylic acid ethyl ester as awhite crystal. Yield: 82%.

Mp: 78.5-81.5° C.

NMR(CDCl₃) δ 1.44(t, 3H, J=7.2 Hz) 3.06(s, 6H) 4.50(q, 2H, J=7.2 Hz)8.63(s, 1H).

Example 9(1) A Process for the Preparation of1-(1-methoxy-1-methylethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl

To a slurry of 0.71 g (5 mmol) of 1H-1,2,4-triazole-3-carboxylic acidethyl ester in 3.5 ml of THF was added 26 mg (3 mol %) of benzenesulfonic acid monohydrate. 0.72 g (10 mmol) of 2-methoxypropene wasadded dropwise thereto under ice cooling. The mixture was stirred atroom temperature for 2 hours. The reaction mixture was extracted with 15ml of ethylacetate, washed with a saturated aqueous solution of sodiumbicarbonate, dried over MgSO₄ to give yellow oil. The oil was purifiedwith silica gel chromatography (eluate: hexanelethylacetate=1:1) to give0.50 g of 1-(1-methoxy-1-methylethyl)-1H-1,2,4-triazole-3-carboxylicacid ethyl as a pale yellow oil. Yield: 47%.

NMR(CDCl₃) δ 1.44(t, 3H J=7.2 Hz) 1.84(s, 6H) 3.20(s, 3H) 4.49(q, 2HJ=7.2 Hz) 8.38(s, 1H).

HPLC tR=26.7 min; Column: Inertsil ODS-3 (5 μm) 4.6×250 mm; MobilePhase: phosphate buffer (pH7)/acetonitrile (85:15); Flow Rate: 1.0mL/min Detector: 205 nm.

Compounds described in the following Example 9(2) to 9(5) were preparedin accordance with the same manner of Example 9(1).

Example 9(2) 1-(1-Ethoxyethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl

NMR(CDCl₃) δ 1.20(t, 3H J=7.2 Hz) 1.45(t, 3H J=7.2 Hz) 1.73 (d, 3H J=6.0Hz) 3.41-3.62(m, 2H) 4.50(q, 2H J=7.2 Hz) 5.69(q, 1H J=6.0 Hz) 8.36(s,1H).

Mp: 59-60° C.

Example 9(3) 1-(1-Isobutoxyethyl)-1H-1,2,4-triazole-3-carboxylic acidethyl

NMR(CDCl₃) δ 0.87(d, 3H J=6.9 Hz) 0.88(d, 3H J=6.9 Hz) 1.45(t, 3H J=7.2Hz) 1.73 (d, 3H J=6.0 Hz) 1.77-1.90(m, 1H) 3.14(dd, 1H J=6.6, 9.0 Hz)3.28(dd, 1H J=6.6, 9.0 Hz) 4.49(q, 2H J=7.2 Hz) 5.66 (q, 1H J=6.0 Hz)8.34(s, 1H).

Mp: 67° C.

Example 9(4) 1-(1-Butoxyethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl

NMR(CDC₃) δ 0.88(t, 3H J=6.9 Hz) 1.25-1.40(m, 2H) 1.45(t, 3H J=7.2 Hz)1.45-1.60 (m, 2H) 1.73(d, 3H J=6.0 Hz) 3.34-3.42 (m, 1H) 3.46-3.54 (m,1H) 4.50(q, 2H J=7.2 Hz) 5.67 (q, 1H J=6.0 Hz) 8.35(s, 1H).

Mp: 42-43° C.

Example 9(5) 1-(1-Propoxyethyl)-1H-1,2,4-triazole-3-carboxylic acidethyl

NMR(CDCl₃) δ 0.89(t, 3H J=6.9 Hz) 1.45(t, 3H J=7.2 Hz) 1.45-1.60 (m, 2H)1.73(d, 3H J=6.0 Hz) 3.34-3.42 (m, 1H) 3.46-3.54 (m, 1H) 4.50(q, 2HJ=7.2 Hz) 5.67 (q, 1H J=6.0 Hz) 8.35(s, 1H).

Mp: 31-32° C.

Example 10 A Process for the Preparation of1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenoneExample 10(1) Example of Using Trityl as a Protecting Group

To a solution of 624 g (2.86 mol) of 5-(4-fluorobenzyl)-2-acetylfuran in3.0 L of tetrahydrofuran was added at −32 to −25° C. 5.72 L (2.0 eq) ofa solution of 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran.The mixture was stirred at the same temperature for 1.5 hours. 11.2 L ofa solution of 1.26 kg (1.15 eq) of1-trityl-3-ethoxycorbonyl-1,2,4-triazole in tetrahydrofuran was addedthereto at −32 to −7° C. The reaction mixture was stirred at 25° C. for2 hours, poured into diluted hydrochloric acid and extracted withethylacetate. The organic layer was washed with water and evaporatedunder reduced pressure to give a slurry. The crystal was filtered togive 1.53 kg of a protective form. Yield: 95.8%.

The crystal was suspended in 7.5 L of dioxane and mixed with 2.74 L (3.0eq) of 1.5 N hydrochloric acid. The mixture was stirred at 70° C. for 1hour. After cooling, 2.74 L (3.0 eq) of 1.5 N sodium hydroxide was addedthereto and the precipitated crystal was filtered. The crystal wassuspended in ethylacetate and dissolved in a diluted aqueous solution ofsodium hydroxide. After the separation of water layer, an aqueoussolution was acidified with concentrated hydrochloride to pH 4. Theprecipitated crystal was filtered and recrystallized fromtetrahydrofuran/ethylalcohol to give 548 g of the titled compound.Yield: 64%.

Mp: 183-185° C.

Elementary analysis for C₁₆H₁₂FN₃O₃; Calcd (%): C, 61.34; H, 3.86; N,13.41; F, 6.06. Found (%): C, 61.22; H, 3.72; N, 13.41; F, 6.03.

NMR(d₆-DMSO) δ 4.15(2H, s), 6.47(1H, d, J=3.3 Hz), 6.93(1H, s), 7.17(2H,t, J=9.0 Hz), 7.31-7.37(2H, m), 7.50(1H, d, J=3.3 Hz), 8.70(1H, brs).

Example 10(2) Example of Using tetrahydropyran-2-yl as a ProtectingGroup

Example 10(2-1)

To a solution of 0.70 g (3.2 mmol) of 2-acetyl-5-(4-fluorobenzyl)furanand 0.72 g (3.2 mmol) of1-(tetrahydropyran-2-yl)-1-1,2,4-triazole-3-carboxylic acid ethyl esterin 7 ml of THF was added dropwise under ice-cooling 0.64 g (3.2 mmol) ofa 28% solution of sodium methoxide in methanol. The mixture was stirredat room temperature for 14 hours. The reaction mixture was mixed with 20ml of a 1.8% aqueous solution of acetic acid and extracted with 30 ml ofethylacetate. The extract was washed with a saturated sodiumhydrogencarbonate aqueous solution and water, dried over Na₂SO₄ andevaporated under reduced pressure to give 1.4 g of oil. The obtained oilwas crystallized from isopropylalcohol to give 0.77 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-yl]propenoneas a pale yellow crystal. Yield: 61%.

Mp: 128-130° C.

NMR(CDCl₃) δ 1.66-1.76(m, 3H) 2.03-2.08(m, 2H) 2.21-2.27(m, 1H)3.70-3.78(m, 1H) 3.99-4.13(m, 1H) 4.04(s, 2H) 5.55(dd, 1H, J=3.0,9.0 Hz)6.15(d, 1H, J=3.3 Hz) 6.99-7.25(m, 5H) 7.02(s, 1H) 8.36(s, 1H).

A mixture of 0.40 g (1 mmol) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-yl]propenone,2 ml of 1 N diluted hydrochloric acid and 2 ml of methanol was stirredat 75° C. for 2 hours. The reaction mixture was cooled to roomtemperature and stirred under ice cooling for 15 minutes. Theprecipitated crystal was filtered and washed with methanol to give 0.29g of1-[5-(4-fluorobenzyl)furan-2-yl])3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenoneas a pale yellow crystal. Yield: 93%.

Example 10(2-2)

1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-yl]propenonewas prepared in accordance with the same method of Example 10(2-1) andreacted with concentrated hydrochloric acid/isopropylalcohol to isolate1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonehydrochloride. The obtained hydrochloride salt was dissolved in aqueousTHF. The precipitated crystal was filtered to give1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

Example 10(2-3)

1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(tetrahydropyran-2-yl)-1,2,4-triazole-3-yl]propenonewas prepared in accordance with the same method of Example 10(2-1),reacted with concentrated hydrochloric acid/methanol to isolate1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonehydrochloride. The obtained hydrochloride salt was dissolved in aqueousTHF and neutralized with one mole equivalent of sodium carbonate. Theprecipitated crystal was filtered to give1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone.

Example 11(1) Process for the Preparation of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-methoxy-1-methylethyl)-1H-1,2,4-triazole-3-yl]propeuone

A slurry of 7.06 g (50 mmol) of 1H-1,2,4-triazole-3-carboxylic acidethyl ester in 35 ml of toluene was added 0.38 g (3 mol %) ofp-toluenesulfonic acid pyridinium salt monohydrate. 4.69 g (65 mmol) of2-methoxypropene was added dropwise at room temperature thereto. Themixture was stirred at 45° C. for 2 hours. After that, 10.91 g (50 mmol)of 2-acetyl-5-(4-fluorobenzyl)furan and 35 ml of THF were added theretoand then 13.5 ml (65 mmol) of a 28% solution of sodium methoxide inmethanol was added dropwise under ice-cooling. The reaction mixture waswarmed up to 60° C. and stirred for 3 hours. The reaction mixture wascooled to room temperature and kept standing overnight. To the solutionwas added dropwise under ice cooling 28.5 g of a 13.7% solution ofacetic acid. The organic layer was separated. The extract was washedwith 28.5 g of 5% brine, concentrated at 45° C. under 50 mmHg to give26.71 g of an oil. The residue was crystallized from 42 ml ofisopropylalcohol to give 14.58 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-methoxy-1-methylethyl)-1H-1,2,4-triazole-3-yl]propenoneas yellow crystal. Yield: 75.7%.

NMR(CDCl₃) δ 5 1.86(s, 6H) 3.22(s, 3H) 4.05(s, 2H) 6.16(d, 1H, J=3.3 Hz)6.99-7.05(m, 2H) 7.02(s, 1H) 7.20-7.25(m, 3H) 8.38(s, 1H).

Mp: 111° C.

The following compounds described in Example 11(2) to 11(5) wereprepared in accordance with the same manner of Example 11(1).

Example 11(2)1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-ethoxyethyl)-1H-1,2,4-triazole-3-yl]propenone

NMR(CDCl₃) δ 1.20(t, 3H J=7.2 Hz) 1.75(d, 3H J=6.0 Hz) 3.44-3.63(m, 2H)4.05(s, 2H) 5.69 (q, 1H J=6.0 Hz) 6.16 (d, 1H J=3.3 Hz) 6.99-7.05(m, 2H)7.02(s, 1H) 7.20-7.26(m, 3H) 8.35(s, 1H).

Mp: 85-87° C.

Example 11(3)1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-isobutoxyethyl)-1H-1,2,4-triazole-3-yl]propenone

NMR(CDCl₃) δ 0.88(d, 3H J=6.6 Hz) 0.89(d, 3H J=6.6 Hz) 1.75(d, 3H J=6.0Hz) 1.78-1.91(m, 1H) 3.17(dd, 1H J=6.6, 9.0 Hz) 3.29(dd, 1H J=6.6, 9.0Hz) 4.05(s, 2H) 5.66 (q, 1H J=6.0 Hz) 6.16 (d, 1H J=3.3 Hz) 6.99-7.05(m,2H) 7.02(s, 1H) 7.20-7.25(m, 3H) 8.34(s, 1H).

Mp: 70° C.

Example 11(4)1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-butoxyethyl)-1H-1,2,4-triazole-3-yl]propenone

NMR(CDCl₃) δ 0.89(t, 3H J=7.2 Hz) 1.27-1.37(m, 2H) 1.50-1.59(m, 2H)1.75(d, 3H J=6.0 Hz) 3.47-3.53(m, 2H) 4.05(s, 2H) 5.67 (q, 1H J=6.0 Hz)6.16 (d, 1H J=3.3 Hz) 6.99-7.05(m, 2H) 7.02(s, 1H) 7.20-7.26(m, 3H)8.34(s, 1H).

IR(neat)=3117, 2960, 2935, 2874, 1736, 1714, 1606 cm⁻¹.

Example 11(5)1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-[1-(1-propoxyethyl)-1H-1,2,4-triazole-3-yl]propenone

NMR(CDCl₃) δ 0.90(t, 3H J=7.2 Hz) 1.53-1.65(m, 2H) 1.75(d, 3H J=6.0 Hz)3.33-3.41(m, 1H) 3.44-3.52(m, 1H) 4.05(s, 2H) 5.68 (q, 1H J=6.0 Hz) 6.16(d, 1H J=3.3 Hz) 6.99-7.05(m, 2H) 7.02(s, 1H) 7.20-7.25(m, 3H) 8.35(s,1H).

Mp: 67-68° C.

Example 121-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-4-triazole-3-yl)propenone

A solution of 4 g (10.4 mmol) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-1-(1-methoxy-1-methylethyl)-1,2,4-triazole-3-yl]propenonein 10.2 ml of a 2% aqueous solution of sulfuric acid and 30 ml ofmethanol were stirred at 60° C. for 1 hour. The solution was cooled andstirred at room temperature for 1 hour. A precipitated crystal wasfiltered off and washed with 20 ml of 75% methanol to give 2.72 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenoneas a pale yellow crystal.

Yield: 83.4%.

1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1NH-1,2,4-triazole-3-yl)propenonewas prepared from a compound obtained in Example 11(2)-11(6) afterdeprotection such as Example 12.

Example 13(1) A Preparation of a Crystal (Type I) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone

712 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonewas dissolved in 7 L of THF under heating. The obtained solution wasfiltered and washed with 2 L of THF. The obtained solution wasconcentrated under reduced pressure and 17 L. of 99.5% EtOH wasgradually added thereto. The solution was concentrated under reducedpressure to give 8.3 kg of the residue. The obtained slurry was stirredfor 1 hour under water-cooling and filtered to give 548 g of a crystal(type I). According to single crystal X-ray diffraction, a crystal (typeI) was a isomer having a chemical structure of the formula:

Elementary analysis for C₁₆H₁₂FN₃O₃. Calcd (%): C, 61.34; H, 3.86; N,13.41; F, 6.06. Found (%): C, 61.22; H, 3.72; N, 13.41; F, 6.03.

Crystal parameters of single crystal X-ray diffraction Unit cellconstants: a = 32.432(2)Å b = 10.886(2)Å c = 7.960(2)Å α = 90.00° β =90.00° γ = 90.00° V = 2810(1)Å³ Z = 8 Space group: Pbca Density: 1.481g/cm³ Diffraction angles (2θ) and intensities of main peaks of powderX-ray diffraction of a crystal (type I) Diffraction angle (2θ) Intensity20.380 5945 21.280 5455 21.340 4958 23.140 4053 23.360 7218 23.540 817325.860 4615 27.460 4138 27.500 4068 28.100 5143 28.180 4980 29.400 452829.480 4848 Differential scanning calorimetry Peak (° C.) ΔH (J/g)185.831 149.181

Example 13(2) A Preparation of a Crystal (Type I) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone

4 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonewas dissolved under heating in 21.2 ml of THF/H₂O (50:3). The obtainedsolution was filtered and 40 ml of THF/H₂O (3:94) 40 ml was graduallyadded thereto. The obtained slurry was stirred for 1 hour underwater-cooling, filtered and washed with water to give a crystal (typeI). A crystal obtained from this Example showed the same date of eachinstrumental analysis of a crystal (type I) obtained from Example 13(1).

Example 13(3) A Preparation of a Crystal (Type II) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone

2 g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonewas dissolved in 600 ml of ethylacetate under heating. The solution wasfiltered, kept standing at room temperature and dried under usualpressure. The obtained crystal was washed with ethylacetate to give acrystal (type II). Judging from a data of single crystal X-raydiffraction, a crystal (type II) was a isomer having a structure of theformula:

Crystal parameters of single crystal X-ray diffraction Unit cellconstants: a = 11.9003(7)Å b = 9.7183(5)Å c = 13.2617(8)Å α = 90.00° β =109.450(4)° γ = 90.00° V = 1446.2(1)Å³ Z = 4 Space group: P2₁/n Density:1.439 g/cm³ Diffraction angles (2θ) and intensities of main peaks ofpowder X-ray diffraction of a crystal (type II) Diffraction angle (2θ)Intensity 8.760 12805 19.600 8023 22.080 8473 23.760 20195 26.200 3323527.580 11623 29.080 4913 Diffrential scanning calorimetry Peak (° C.) ΔH(J/g) 177.8 142.09 184.07 3.616

Example 13(4) A Preparation of a Crystal (III) of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone

To 1g of1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenonehydrochloride was added methanol (10 ml). After heating and stirring,methanol was concentrated under reduced pressure. Methanol (10 ml) wasadded to the residue and concentrated as well as the above again.Moreover, methanol (10 ml) was added to the residue and concentrated aswell as the above again. The obtained slurry was kept standingovernight. A crystal was isolated and washed with methanol to give acrystal (type III).

Elementary analysis for C₁₆H₁₂FN₃O₃.

Calcd: C, 61.43; H, 3.86; F, 6.06; N, 13.41; Cl 0.00.

Found: C, 60.23; H, 3.98; F, 5.85; N, 13.38; Cl<0.10.

Diffraction angles (2θ) and intensities of main peaks of powder X-raydiffraction of a crystal (type III) Diffraction angle (2θ) Intensity10.520 4020 13.860 10368 15.680 11768 18.160 4363 22.840 6723 26.1806335 28.120 3928 Diffrential scanning calorimetry Peak (° C.) ΔH (J/g)130.8 −9.116 186.13 144.3

An another process for the preparation of2-acetyl-5-(4-fluorobenzyl)furan are described below.

Example 14(1) A Process for the Preparation of2-acetyl-5-(4-fluorobenzyl)furan (Another Route 1)

(1) 5.6 g (50 mmol) of 2-furancarboxylic acid was reacted with 6.8 g (55mmol) of 4-fluoro benzasdehyde in accordance with Tetrahedron Letters,1979, 51, p469. The obtained crude crystal was washed with isopropylether to give 8.1 g of5-[[1-(4-fluorophenyl)-1-hydroxy]methyl]-furan-2-carboxylic acid. Yield:69%. Mp: 139-140° C. (decomposition).

NMR(CDCl₃) δ 5.88(1H, s), 6.28(1H, d, J=3.6 Hz), 7.07(2H, t, J=8.7 Hz),7.25(1H, d, J=3.6 Hz), 7.39-7.44(2H, m).

(2) 4.72 g (20 mmol) of the compound was reduced with 10.8 g (100 mmol)of trimethylchlorosilane and 15 g (100 mmol) of sodium iodide inaccordance with Tetrahedron, 1995, 51, p11043 to give 3.52 g of5-(4-fluorobenzyl)-furan-2-carboxylic acid as a crystal. Yield: 80%.

NMR(d6-DMSO) δ 4.05(2H, s), 6.31(1H, d, J=3.3 Hz), 7.12-7.18(3H, m),7.27-7.32(2H, m), 12.9(1H, brs).

(3) 3.52 g (16 mmol) of the above compound was reacted with 4.2 g (19.2mmol) of dipyridyldisulfide and 5.04 g (19.2 mmol) of triphenytphosphinein accordance with Bull. Chem. Soc. Japan., 1974, 47, p1777 to give 3.7g of 5-(4-fluorobenzyl)-furan-2-carboxylic acid 2-pyridylthioester.Yield: 77%. Mp: 88-89° C.

NMR(CDCl₃) δ 4.04(2H, s), 6.15(1H, d, J=3.3 Hz), 7.03(2H, t, J=8.7 Hz),7.22(1H, d, J=3.3 Hz), 7.22-7.26(2H, m), 7.29-7.34(1H, m), 7.70-7.79(2H,m), 8.63-8.66(1H, m).

(4) 3.7 g (12.4 mmol) of the above compound was reacted with 14 ml (1 M)of methyl magnesium bromide in accordance with Bull. Chem. Soc. Japan.,1974, 47, p1777 to give 2.7 g of 2-acetyl-5-(4-fluorobenzyl)-furan as anoil(2.7 g) quantitatively.

NMR(CDCl₃) δ 2.43(3H, s), 4.01(2H, s), 6.10(1H, d, J=3.6 Hz), 7.01(2H,t, J=9.0 Hz), 7.10(1H, d, J=3.6 Hz), 7.18-7.23(2H, m).

Example 14(2) A process for the Preparation of2-acetyl-5-(4-fluorobenzyl)furan (Another Route 2)

(1) LDA in 27.5 ml (25% solution, 30 mmol) of a mixed solution(THF/heptanelethylbenzene) was cooled to −50° C. and 7.5 ml (30 mmol) oftetramethylethylenediamine was added thereto. To the mixture was addedwith stirring under −45° C. for 25 minutes 2.24 g (20 mmol) of2-furancarboxylic acid in 12 ml of THF. After stirring for 1 hour at−50° C., 40 ml of THF was added to the obtained suspension. 3.8 ml (35mmol) of 4-fluorobenzaldehyde was immediately added thereto. Thereaction temperature rose from 50 to −15° C. After stirring underice-cooling for 30 minutes, 40 ml of water was added thereto. Theorganic layer was extracted with 1N sodium hydroxide aqueous solution.The obtained alkaline layer was washed with toluene, acidified withdiluted hydrochloric acid and extracted with ethylacetate. The extractwas washed with water, dried over anhydrous sodium sulfate and removedunder reduced pressure. The obtained residue was crystallized fromtoluene and washed with cooled toluene to give a 4.29 g of hydroxycarboxylic acid. Yield: 91%.

(2) To a solution of 1.18 g (5 mmol) of hydroxy carboxylic acid and 1.52g (15 mmol) of triethylamine in 15 ml of ethylacetate was added dropwiseunder ice-cooling a solution of 1.16 g (11.4 mmol) of acetic anhydridein 1 ml of ethylacetate. The solution was stirred under ice cooling for30 minutes. 253 mg (2.5 mmol) of triethylamine and 180 mg of 10%palladium carbon were added thereto. The suspension was stirred athydrogen atmosphere under usual pressure for 4.5 hours. The catalyst wasfiltered off. Dilute hydrochloric acid was added to the filtrate andextracted with ethylacetate. The extract was washed with water, driedover anhydrous magnesium sulfate and removed under reduced pressure. Theobtained residue was crystallized from n-hexane and washed with n-hexaneto give 991 mg of carboxylic acid. Yield: 90%.

(3) To a suspension of 1.00 g (4.54 mmol) of carboxylic acid in 5 ml oftoluene were added 648 mg (5.44 mmol) of thionylchloride and 0.03 ml ofDMF. The suspension was stirred at 80° C. for 1.5 hours. The solvent andexcess of thionylchloride were removed under reduced pressure, mixedwith 5 ml of toluene and removed under reduced pressure. To the obtainedresidue were added 10 ml of THF and 48 mg (0.12 mmol) of ironic acetylacetonate (Fe(acac)₃). The solution was cooled at −20° C. To thesolution was added dropwise for 10 minutes 1.75 ml (5.25 mmol) of 3Mmethyl magnesium chloride in THF with stirring at nitrogen atmosphere.The mixture was stirred at −20° C. for 30 minutes, mixed with dilutedhydrochloric acid and extracted with toluene. The extract was washedwith water, washed with sodium hydrogencarbonate aqueous solution,washed with water and removed under reduced pressure to give 1.02 g of2-acetyl-5-(4-fluorobenzyl)furan. Yield: quantitative.

The following compounds are prepared in accordance with the presentprocess.

1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(2H-tetrazole-5-yl)-propenone

Mp: 121-123° C. Recrystallized from ether.

Elementary analysis for C₁₅H₁₁FN₄O₃; Calcd (%): C, 57.33; H, 3.53; N,17.83; F, 6.04. Found (%): C, 57.25; H, 3.58; N, 17.53; F, 5.81.

NMR(d₆-DMSO) δ 4.16(2H, s), 6.51(1H, d, J=3.6 Hz), 7.05(1H, s), 7.18(2H,t, J=8.7 Hz), 7.32-7.38(2H, m), 7.65(1H, d, J=3.6 Hz).

1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(5-methyl-1H-[1,2,4]-triazole-3-yl)-propenone.

Mp: 179-182° C. Recrystallized from ethylacetate.

Elementary analysis for C₁₇H₁₄FN₃O₃; Calcd (%); C, 62.38; H, 4.31; N,12.84; F, 5.80. Found (%): C, 62.29; H, 4.16; N, 11.65; F, 5.78.

NMR(d₆-DMSO) δ 2.43(3H, s), 4.14(2H, s), 6.46(1H, d, J=3.3 Hz), 6.88(1H,s), 7.15-7.20(2H, m), 7.31-7.36(2H, m), 7.49(1H, d, J=3.3 Hz), 14.3(1H,brs).

1-[5-(4-Chlorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-[1,2,4]triazole-3-yl)-propenone

Mp: 96-99° C. Recrystallized from ethanol.

Elementary analysis for C₁₆H₁₂ClN₃O₃; Calcd (%): C, 58.28; H, 3.67; N,12.74; Cl, 10.75. Found (%): C, 58.16; H, 3.80; N, 12.40; Cl, 10.50.

NMR(d₆-DMSO) δ 4.16(2H, s), 6.49(1H, d, J=3.6 Hz), 6.93(1H, s),7.30-7.43(4H, m), 7.52(1H, d, J=3.6 Hz), 8.75(1H, brs).

1-(5-Benzylfuran-2-yl)-3hydroxy-3-(1H-[1,2,4]triazole-3-yl)-propenone

Mp: 176-179° C. Recrystallized from ethylacetate.

Elementary analysis for C₁₆H₁₃N₃O₃ 0.15 C₄H₈O₂ Calcd (%): C, 64.63; H,4.64; N, 13.62. Found (%): C, 64.41; H, 4.40; N, 13.42.

NMR(d₆-DMSO) δ 4.14(2H, s), 6.48(1H, d, J=3.6 Hz), 6.93(1H, s),7.24-7.38(5H, m), 7.51(1H, d, J=3.6 Hz), 8.72(1H, brs), 14.7(1H, brs).

1-[[5-(4-Fluorobenzyl)-3-methyl]furan-2-yl]-3-hydroxy-3-(1H-[1,2,4]triazole-3-yl)-propenone.

Mp: 191-192° C. Recrystallized from ethylacetate.

Elementary analysis for C₁₇H₁₄FN₃O₃. Calcd (%): C, 62.38; H, 4.31; N,12.84; F, 5.80. Found (%): C, 62.23; H, 4.29; N, 12.79; F, 5.79.

NMR(d₆-DMSO) δ 2.36(3H, s), 4.10(2H, s), 6.34(1H, s), 6.89(1H, s),7.18(2H, t, J=9.0 Hz), 7.32-7.37(2H, m), 8.70(1H, brs).

3-Hydroxy-1-[5-(4-methoxybenzyl)furan-2-yl]-3-(1H-[1,2,4]triazole-3-yl)-propenone.

Mp: 114-116° C. Recrystallized from ethylacetate.

Elementary analysis for C₁₇H₁₅N₃O₄; Calcd (%): C, 62.76; H, 4.65; N,12.92. Found (%): C, 62.90; H, 4.57; N. 12.26.

NMR(d₆-DMSO) δ 3.73(3H, s), 4.07(2H, s), 6.44(1H, d, J=3.3 Hz), 6.91(2H,d, J=8.7 Hz), 6.92(1H, s), 7.22(2H, d, J=8.7 Hz), 7.50(1H, d, J=3.3 Hz),8.77(1H, brs).

1-[5-(3-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-[1,2,4]triazole-3-yl)-propenone.

Mp: 140-143° C. Recrystallized from ethanol.

Elementary analysis for C₁₆H₁₂FN₃O₃; Calcd (%): C, 61.34; H, 3.86; N,13.41; F, 6.06. Found (%): C, 61.41; H, 3.84; N, 13.05; F, 5.97.

NMR(d₆-DMSO) δ 4.19(2H, s), 6.52(1H, d, J=3.3 Hz), 6.95(1H, s),7.10-7.18(3H, m), 7.36-7.41(1H, m), 7.52(1H, d, J=3.3 Hz), 8.77(1H,brs), 14.7(1H, brs).

1-[5-(2-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-[1,2,4]triazole-3-yl)-propenone

Mp: 182-184° C. Recrystallized from ethanol/ether.

Elementary analysis for C₁₆H₁₂FN₃O₃; Calcd (%): C, 61.34; H, 3.86; N,13.41; F, 6.06. Found (%): C, 61.47; H, 3.90; N, 13.04; F, 5.99.

NMR(d₆-DMSO) δ 4.18(2H, s), 6.46(1H, d, J=3.3 Hz), 6.94(1H, s),7.17-7.26(2H, m), 7.32-7.40(2H, m), 7.51(1H, d, J=3.3 Hz), 8.79(1H,brs).

3-Hydroxy-1-[5-(4-methylbenzyl)furan-2-yl]-3-(1H-[1,2,4]triazole-3yl)-propenone.

Mp: 166-167° C. Recrystallized from ethylacetate.

Elementary analysis for C₁₇H₁₅N₃O₃ 0.1 C₄H₈O₂; Calcd (%): C, 65.69; H,5.01; N, 13.21. Found (%): C, 65.45; H, 4.93; N, 13.37.

NMR(d₆-DMSO) δ 2.28(3H, s), 4.09(2H, s), 6.46(1H, d, J=3.6 Hz), 6.93(1H,s), 7.13-7.18(4H, m), 7.51(1H, d, J=3.6 Hz), 8.76(1H, brs), 14.7(1H,brs).

HIV-1 integrase inhibitory activities of propenone derivatives wereexamined in accordance with the following assay.

(1) Preparation of DNA Solutions.

Substrate DNA and target DNA, which sequences were indicated below, weresynthesized by Amersham Pharmacia Biotech and dissolved in KTE buffer(composition: 100 mM KCl, 1 mM EDTA, 10 mM Tris-HCl (pH 7.6)) atconcentration of 2 pmol/μl and 5 pmol/μl, respectively. The DNAsolutions were annealed with each complement by slowly cooling afterheating.

(Substrate DNA)

5′-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG CAG T-3′

3′-GAA AAT CAG TCA CAC CTT TTA GAG ATC GTC A-5′

(Target DNA)

5′-TGA CCA AGG GCT AAT TCA CT-Dig-3′

3′-Dig-ACT GGT TCC CGA TTA AGT GA-5′

(2) Calculations of the Percent Inhibitions (the IC₅₀ Values of TestCompounds)

Streptavidin, obtained from Vector Laboratories, was dissolved in 0.1 Mcarbonate buffer (composition: 90 mM Na₂CO₃, 10 mM NaHCO₃) atconcentration of 40 μg/ml. After coating each well of microtiter plates(obtained from NUNC) with 50 μl of the above solution at 4° C. overnight, each well was washed twice with PBS (composition: 13.7 mM NaCl,0.27 mM KCl, 0.43 mM Na₂HPO₄, 0.14 mM KH₂PO₄) and blocked with 300 μl of1% skim milk in PBS for 30 min. Additionally, each well was washed twicewith PBS and added 50 μl of substrate DNA solution (2 pmol/μl). Themicrotiter plates were kept at room temperature for 30 min. Then, eachwell was washed twice with PBS and once with H₂O.

Subsequently, in the each well prepared above were added 45 μl of thereaction buffer prepared from 12 μl of the buffer (composition: 150 mMMOPS (pH 7.2), 75 mM MnCl₂, 50 mM 2-mercaptoethanol, 25% glycerol, 500μg/ml bovine serum albumin-fraction V), 1 μl of target DNA (5 pmol/μl),and 32 μl of the distilled water. Additionally, 6 μl of either a testcompound in DMSO or DMSO for positive control(PC) was mixed with theabove reaction buffer, then 9 μl of an integrase solution (30 pmol) wasadded and mixed well. In the well of negative control (NC) was added 9μl of the integrase dilution buffer (composition: 20 mM MOPS (pH_(7.2)),400 mM potassium glutamate, 1 mM EDTA, 0.1% NP-40, 20% glycerol, 1 mMDTT, 4M urea).

The microtiter plates were incubated at 30° C. for 1 hour. The reactionsolution was removed and each well was washed twice with PBS.Subsequently, each well of the microtiter plates was filled with 100 μlof anti-digoxigenin antibody labeled with alkaline phosphatase (SheepFab fragment: obtained from Boehringer) and incubated at 30° C. for 1hour. Then, each well was washed twice with 0.05% Tween20 in PBS andonce with PBS. Next, 150 μl of the Alkaline phosphatase reaction buffer(composition: 10 mM p-Nitrophenylphosphate (obtained from VectorLaboratories), 5 mM MgCl₂, 100 mM NaCl, 100 mM Tris-HCl (pH 9.5))wasadded in each well. The microtiter plates were incubated at 30° C. for 2hours and the reaction was terminated by the addition of 50 μl of 1 NNaOH solution. The optical density (OD) at 405 nm of each well wasmeasured and the percent inhibition was determined by the followingexpression.

The percent inhibition (%)=100 [1-{(C abs.-NC abs.)/(PC abs.-NC abs.)}]

C abs.; the OD of the well of the compounds

NC abs.: the OD of the negative control (NC)

PC abs.: the OD of the positive control (PC)

When the percent inhibition (%) is X% at the concentration of x μg/mland the percent inhibition (%) is Y% at the concentration of y μg/ml,one of which is more than 50% and the other is less than 50%, IC₅₀ canbe determined by the following expression.

IC₅₀(μg/ml)=x-{(X-50)(x-y)/(X-Y)}

The IC₅₀ values, the concentration of the compounds at percentinhibition 50%, are shown in the following Table 1.

TABLE Compound No. IC₅₀(μg/ml) 22 0.53

INDUSTRIAL APPLICABILITY

2-Acyl-5-benzylfuran derivatives can be industrially and commerciallyprepared through Friedel Crafts reaction of 2-acylfuran derivatives. Thepresent invention provides an industrial process for the preparation of1,2,4-triazole-3-carboxylic acid ester derivatives. These processes cancontribute to stable mass-production of an integrase inhibitor, ananti-HIV agent, or a compound (IV-1) or (IV-2).

What is claimed is:
 1. A compound of the formula (IV-9):

wherein R⁶ is hydrogen; R¹³ is alkyl, a group of the formula: —R⁷wherein R⁷ is trityl, optionally substituted sulfamoyl or alkoxymethyl,a group of the formula: C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸ is alkyl; R⁹, R¹⁰and R¹¹ each is independently hydrogen or alkyl; or R⁸ and R¹⁰ may betaken together to form alkylene, or hydroxymethyl; and R¹⁴ is a group ofthe formula: —R⁷ wherein R⁷ is as defined above, a group of the formula:—C(OR⁸)R⁹—CHR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ are defined above, orhydroxymethyl, provided that a compound wherein R⁶ is hydrogen; R¹³ ismethyl; and R¹⁴ is trityl, a compound wherein R⁶ is hydrogen; R¹³ ismethyl; and R¹⁴ is tetrahydropyran-2-yl, and a compound wherein R⁶ ishydrogen; R¹³ is ethyl; and R¹⁴ is trityl are excluded.
 2. The compoundaccording to claim 1 wherein R⁶ is hydrogen; R¹³ is methyl or ethyl; R¹⁴is tetrahydropyran-2-yl, hydroxymethyl, methoxymethyl, ethoxymethyl,N,N-dimethylsulfamoyl, (1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl,(1-ethoxy-1-methyl)ethyl, (1-n-propoxy)ethyl, (1-n-butoxy)ethyl or(1-isobutoxy)ethyl.
 3. A process for the preparation of a compound ofthe formula (IV-9):

wherein R⁶, R¹³ and R¹⁴ are as defined in claim 1, provided that acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ is trityl, acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ istetrahydropyran-2-yl, and a compound wherein R⁶ is hydrogen; R¹³ isethyl; and R¹⁴ is trityl are excluded, which comprises reacting acompound of the formula (IV-5-1):

wherein R⁶ and R¹³ are as defined in claim 1, with a compound of theformula: R⁷X wherein R⁷ is as defined in claim 1; and X is halogen, acompound of the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹are as defined in claim 1, or formaldehyde.
 4. A process of thepreparation of a compound of the formula (IV-9):

wherein R⁶, R¹³ and R¹⁴ are as defined in claim 1, provided that acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ is trityl, acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ istetrahydropyran-2-yl, and a compound wherein R⁶ is hydrogen; R¹³ isethyl; and R¹⁴ is trityl are excluded, which comprises reacting acompound of the formula (IV-7):

wherein R⁶ is as defined in claim 1, with a compound of the formula: R⁷Xwherein R⁷ is as defined in claim 1; and X is halogen, a compound of theformula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸, R⁹, R¹⁰ and R¹¹ are as defined inclaim 1, or formaldehyde.
 5. The process according to claim 3 or 4 whichcomprises reacting with a compound of the formula: R⁷X wherein R⁷ istrityl.
 6. The process according to claim 3 or 4 which comprisesreacting with a compound of the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸ andR¹⁰ are taken together to form trimethylene; and R⁹ and R¹¹ each ishydrogen.
 7. The process according to claim 3 or 4 which comprisesreacting with a compound of the formula: (R⁸O)R⁹C═CR¹⁰R¹¹ wherein R⁸ andR⁹ each is methyl; and R¹⁰ and R¹¹ each is hydrogen.
 8. A process forthe preparation of a compound of the formula (VI-2):

wherein R¹, R² and R⁴ each is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy or halogen; and R⁶ ishydrogen, optionally substituted alkyl or optionally substituted aryl,which comprises reacting a compound of the formula (IV-9):

wherein R⁶, R¹³ and R¹⁴ are as defined in claim 1, provided that acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ is trityl, acompound wherein R⁶ is hydrogen; R¹³ is methyl; and R¹⁴ istetrahydropyran-2-yl, and a compound wherein R⁶ is hydrogen; R¹³ isethyl; and R¹⁴ is trityl are excluded, with a compound of the formula(III-2):

wherein R¹, R² and R⁴ are as defined above, and deprotecting R¹⁴.
 9. Theprocess according to claim 8 wherein R¹, R² and R⁶ each is hydrogen; andR⁴ is halogen.